Urokinase inhibitors

ABSTRACT

Compounds having the formula                    
     are inhibitors of urokinase and are useful in the treatment of diseases in which urokinase plays a role. Also disclosed are urokinase-inhibiting compositions and a method of inhibiting urokinase in a mammal.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation-in-part of Provisional U.S.Application Ser. No. 60/054,982, filed Aug. 6, 1997, pending.

BACKGROUND OF THE INVENTION

The present invention provides naphthamidine compounds which inhibit theurokinase enzyme, pharmaceutical compositions containing these compoundsand medical methods of treatment using these compounds.

TECHNICAL FIELD

Urokinase (urinary-type plasminogen activator or uPA (InternationalUnion of Biochemistry classification number: EC3.4.21.31)) is aproteolytic enzyme which is highly specific for a single peptide bond inplasminogen. Plasminogen activation (cleavage of this bond by theurokinase enzyme) results in formation of plasmin, a potent generalprotease.

Many cell types use urokinase as a key initiator of plasmin-mediatedproteolytic degradation or modification of extracellular supportstructures such as extracellular matrix (ECM) and basement membrane(BM). Cells exist, move and interact with each other in tissues andorgans within the physical framework provided by ECM and BM. Movement ofcells within ECM or across BM requires local proteolytic degradation ormodification of the structures and allows cells to invade adjacent areaspreviously unavailable prior to the degredation or modification.

Cellular invasiveness intiated by urokinase is central to a variety ofnormal and disease-state physiological processes (Blasi, F., Vassalli,J. D., and Dano, K. J. Cell Biol. 104:801-804, 1987; Dano, K., Anderson,P. A., Grondahl-Hansen, J., Kristensen, P., Nielsen, L. S., and Skriver,L. Adv. Cancer Res. 44:139-266, 1985; Littlefield, B. A. Ann. N. Y.Acad. Sci. 622: 167-175, 1991; Saksela, O., Biochim. Biophys. Acta 823:35-65, 1985; Testa, J. E. and Quigley, J. P. Cancer Metast. Rev.9:353-367, 1990). Such processes include, but are not limited to,angiogenesis (neovascularization), bone restructuring, embryoimplantation in the uterus, infiltration of immune cells intoinflammatory sites, ovulation, spermatogenesis, tissue remodellingduring wound repair and organ differentiation, fibrosis, tumor invasion,metastatic spread of tumor cells from primary to secondary sites andtissue destruction in arthritis. Amiloride, for example, a knownurokinase inhibitor of only moderate potency, has been reported toinhibit tumor metastasis in vivo (Kellen, J. A., Mirakian, A. Kolin, A.Anticancer Res. 8:1373-1376, 1988) and angiogenesis/capillary networkformation in vitro (Alliegro, M. C. and Glaser, B. M. J. Cell Biol.115[3 Pt 2]: 402a, 1991).

Inhibitors of urokinase, therefore, have mechanism-basedanti-angiogenic, anti-arthritic, anti-inflammatory, anti-retinopathic(for anigiogenesis-dependent retinopathies), contraceptive andtumoristatic uses.

SUMMARY OF THE INVENTION

In its principle embodiment, the present invention provides a compoundor a pharmaceutically acceptable salt, ester or prodrug thereof, offormula (I)

Z is selected from the group consisting of

(1) nitrogen;

(2) methine; and

(3) methine substituted with —NR₁R₂;

A is selected from the group consisting of

(1) hydrogen and

(2) —L_(A)R_(A);

B is selected from the group consisting of

(1) hydrogen and

(2) —L_(B)R_(B) and

C is selected from the group consisting of

(1) hydrogen and

(2) —L_(C)R_(C),

with the proviso that at least one of A, B or C is other than hydrogen;and

with the proviso that when A is other than hydrogen, at least one of Bor C is other than hydrogen,

wherein for A, B, and C, L_(A), L_(B) and L_(C) are independentlyselected from the group consisting of

(1) a covalent bond,

(2) —(CH₂)_(m)—,

(3) —NR₁—,

(4) —NR₂C(X)NR₃—,

(5) —C(X)—,

(6) —NR₂C(X)—,

(7) —C(X)NR₂—,

(8) —CH═CH—,

(9) —C≡C—,

(10) —O—,

(11) —S(O)_(t)—,

(12) —C≡C(CH₂)_(n)NR₂C(X)—,

(13) —C(X)NR₂(CH₂)_(n)C≡C—,

(14) —(CH₂)_(n)NSO₂—,

(15) —NR₂SO₂(CH₂)_(n)C≡C—,

(16) —C≡C(CH₂)_(n)NR₂SO₂NR₃—,

(17) —NR₂SO₂NR₃(CH₂)_(n)C≡C—,

(18) —SO₂NR₂—,

(19) —NR₂SO₂—,

(20) —NR₂SO₂NR₃—,

(21) —N═N—,

(22) —C(X)N(OR₂)—,

(23) —N(OR₂)C(X)—,

(24) —HC═CH(CH₂)_(n)NR₂C(X)—,

(25) —(CH₂)_(n)NR₂C(X)CH═CH—,

(26) —CH═CH(CH₂)_(n)NSO₂—,

(27) —NR₂SO₂(CH₂)_(n)CH═CH—,

(28) —(CH₂)_(n)NR₂SO₂NR₃—,

(29) —NR₂SO₂NR₃(CH₂)_(n)CH═CH—,

(30) —NR₂C(O)O—,

(31) —OC(O)NR₂—,

(32) —CH═NO—,

(33) —ON═CH— and

(34)

wherein W is selected from the group consisting of

(a) —O—,

(b) —S—,

(c) —NR₁— and

(d) —(CH₂)_(m)—,

wherein each functional group is depicted with its tight-hand end beingthe end which is attached to the naphthyl or quinolyl ring and itsleft-hand end being the end which is attached to R_(A), R_(B) or R_(C);

R_(A), R_(B) and R_(C) are independently selected from the groupconsisting of

(1) aryl;

(2) arylalkoxy, wherein the alkylene group is of one to six carbonatoms;

(3) alkyl of one to ten carbon atoms;

(4) alkenyl of two to ten carbon atoms;

(5) alkoxycarbonyl of one to six carbon atoms;

(6) alkynyl of two to ten carbon atoms;

(7) halogen;

(8) —NR₁R₂;

(9) heterocycle;

(10) cycloalkenyl of four to twelve carbon atoms;

(11) cycloalkyl of three to twelve carbon atoms;

(12) —NR₁C(O)NR₂R₃; and

(13) —NR₁C(O)R₅₀, wherein R₅₀ is alkyl of one to six carbon atoms;

wherein, at each occurence, R₁ is selected from the group consisting of

(1) hydrogen;

(2) an N-protecting group;

(3) alkyl of one to six carbon atoms;

(4) alkenyl of two to six carbon atoms;

(5) alkynyl of two to six carbon atoms;

(6) aryl;

(7) arylalkyl, wherein the alkylene group is of one to six carbon atoms;

(8) cycloalkyl of three to eight carbon atoms and

(9) cycloalkylalkyl, wherein the cycloalkyl group is of three to eightcarbon atoms, and the alkylene group is of one to ten carbon atoms; and

wherein, at each occurence, R₂ and R₃ are independently selected fromthe group consisting of

(1) hydrogen;

(2) alkyl of one to six carbon atoms;

(3) alkenyl of two to six carbon atoms;

(4) alkynyl of two to six carbon atoms;

(5) aryl;

(6) arylalkyl, wherein the alkylene group is of one to six carbon atoms

(7) cycloalkyl of three to eight carbon atoms and

(8) cycloalkylalkyl, wherein the cycloalkyl group is of three to eightcarbon atoms, and the alkylene group is of one to ten carbon atoms; and

wherein, at each occurence, X is selected from the group consisting of

(1) O and

(2) S; and

wherein, at each occurence,

m is one to five,

n is zero to four and

t is zero to two; and

wherein, at each occurence, the alkyl, alkenyl, alkynyl, aryl,heterocycle, cycloalkyl, and cycloalkenyl groups are optionallysubstituted.

The present invention also relates to a method of inhibiting urokinasein a mammal, particularly humans, by administering a therapeuticallyeffective amount of a composition comprising a compound of formula (I).

The present invention also relates to pharmaceutical compositions whichcomprise a therapeutically effective amount of a compound of formula (I)in combination with a pharmaceutically acceptable carrier.

DETAILED DESCRIPTION OF THE INVENTION

As used throughout this specification and the appended claims, thefollowing terms have the meanings specified:

The term “alkyl,” as used herein, represents a monovalent group derivedfrom a straight or branched chain saturated hydrocarbon by the removalof a single hydrogen atom and is exemplified by methyl, ethyl, n- andiso-propyl, n-, sec-, iso- and tert-butyl, neopentyl and the like andmay be optionally substituted with one, two, three or four substituentsindependently selected from the group consisting of (1) alkoxy of one tosix carbon atoms; (2) alkylsulfinyl of one to six carbon atoms; (3)alkylsulfonyl of one to six carbon atoms; (4) amino; (5) aryl; (6)arylalkoxy, wherein the alkylene group is of one to six carbon atoms;(7) aryloyl; (8) azido; (9) carboxaldehyde; (10) cycloalkyl of three toeight carbon atoms; (11) halo; (12) heterocycle; (13) (heterocycle)oxy;(14) (heterocycle)oyl; (15) hydroxy; (16) N-protected amino; (17) nitro;(18) oxo; (19) spiroalkyl of three to eight carbon atoms; (20)thioalkoxy of one to six carbon atoms; (21) —CO₂R₂; (22) —C(O)NR₂R₃;(23) —SO₂R₄, wherein R₄ is selected from the group consisting of (a)alkyl, (b) aryl and (c) arylalkyl, wherein the alkylene group is of oneto six carbon atoms; (24) —SO₂NR₅R₆, wherein R₅ and R₆ are independentlyselected from the group consisting of (a) hydrogen, (b) alkyl, (c) aryland (d) arylalkyl, wherein the alkylene group is of one to six carbonatoms; (25) —NR₇R₈, wherein R₇ and R₈ are independently selected fromthe group consisting of (a) hydrogen; (b) an N-protecting group; (c)alkyl of one to six carbon atoms; (d) alkenyl of two to six carbonatoms; (e) alkynyl of two to six carbon atoms; (f) aryl; (g) arylalkyl,wherein the alkylene group is of one to six carbon atoms; (h) cycloalkylof three to eight carbon atoms and (i) cycloalkylalkyl, wherein thecycloalkyl group is of three to eight carbon atoms, and the alkylenegroup is of one to ten carbon atoms, with the proviso that no two groupsare bound to the nitrogen atom through a carbonyl group or a sulfonylgroup.

The term “alkanoyl,” as used herein, represents an alkyl group, asdefined herein, attached to the parent molecular group through acarbonyl group, as defined herein, and is exemplified by formyl, acetyl,propionyl, butanoyl and the like.

The term “alkenyl,” as used herein, represents monovalent straight orbranched chain groups containing a carbon—carbon double bond derivedfrom an alkene by the removal of one hydrogen atom and is exemplified byethenyl, 1-propenyl, 2-propenyl, 2-methyl- 1-propenyl, 1-butenyl,2-butenyl and the like and may be optionally substituted with one, two,three or four substituents independently selected from the groupconsisting of (1) alkoxy of one to six carbon atoms; (2) alkylsulfinylof one to six carbon atoms; (3) alkylsulfonyl of one to six carbonatoms; (4) amino; (5) aryl; (6) arylalkoxy, wherein the alkylene groupis of one to six carbon atoms; (7) aryloyl; (8) azido; (9)carboxaldehyde; (10) cycloalkyl of three to eight carbon atoms; (11)halo; (12) heterocycle; (13) (heterocycle)oxy; (14) (heterocycle)oyl;(15) hydroxy; (16) N-protected amino; (17) nitro; (18) oxo; (19)spiroalkyl of three to eight carbon atoms; (20) thioalkoxy of one to sixcarbon atoms; (21) —CO₂R₂; (22) —C(O)NR₂R₃; (23) —SO₂R₄, wherein R₄ isselected from the group consisting of (a) alkyl, (b) aryl and (c)arylalkyl, wherein the alkylene group is of one to six carbon atoms;(24) —SO₂NR₅R₆, wherein R₅ and R₆ are independently selected from thegroup consisting of (a) hydrogen, (b) alkyl, (c) aryl and (d) arylalkyl,wherein the alkylene group is of one to six carbon atoms; (25) —NR₇R₈,wherein R₇ and R₈ are independently selected from the group consistingof (a) hydrogen; (b) an N-protecting group; (c) alkyl of one to sixcarbon atoms; (d) alkenyl of two to six carbon atoms; (e) alkynyl of twoto six carbon atoms; (f) aryl; (g) arylalkyl, wherein the alkylene groupis of one to six carbon atoms; (h) cycloalkyl of three to eight carbonatoms and (i) cycloalkylalkyl, wherein the cycloalkyl group is of threeto eight carbon atoms, and the alkylene group is of one to ten carbonatoms, with the proviso that no two groups are bound to the nitrogenatom through a carbonyl group or a sulfonyl group.

The term “alkoxy,” as used herein, represents an alkyl group attached tothe parent molecular group through an oxygen atom.

The term “alkoxyalkyl” as used herein, represents an alkyl group towhich is attached an alkoxy group.

The term “alkoxycarbonyl,” as used herein, represents an ester group;i.e. an alkoxy group, attached to the parent molecular group through acarbonyl group and is exemplified by methoxycarbonyl, ethoxycarbonyl andthe like.

The term “alkylene,” as used herein, represents a saturated divalenthydrocarbon group derived from a straight or branched chain saturatedhydrocarbon by the removal of two hydrogen atoms, and is exemplified bymethylene, ethylene, isopropylene and the like.

The term “alkylsulfinyl,” as used herein, represents an alkyl groupattached to the parent molecular group through an —S(O)— group.

The term “alkylsulfinylalkyl,” as used herein, represents an alkylgroup, as defined herein, substituted by a sulfinyl group.

The term “alkylsulfonyl,” as used herein, represents an alkyl groupattached to the parent molecular group through an —SO₂— group.

The term “alkylsulfonylalkyl,” as used herein, represents an alkylgroup, as defined herein, substituted by a sulfonyl group.

The term “alkynyl,” as used herein, represents monovalent straight orbranched chain groups of two to six carbon atoms containing acarbon—carbon triple bond derived from an .alkyne by the removal of onehydrogen atom and is exemplified by ethynyl, 1-propynyl, and the likeand may be optionally substituted with one, two, three or foursubstituents independently selected from the group consisting of (1)alkoxy of one to six carbon atoms; (2) alkylsulfinyl of one to sixcarbon atoms; (3) alkylsulfonyl of one to six carbon atoms; (4) amino;(5) aryl; (6) arylalkoxy, wherein the alkylene group is of one to sixcarbon atoms; (7) aryloyl; (8) azido; (9) carboxaldehyde; (10)cycloalkyl of three to eight carbon atoms; (11) halo; (12) heterocycle;(13) (heterocycle)oxy; (14) (heterocycle)oyl; (15) hydroxy; (16)N-protected amino; (17) nitro; (18) oxo; (19) spiroalkyl of three toeight carbon atoms; (20) thioalkoxy of one to six carbon atoms; (21)—CO₂R₂; (22) —C(O)NR₂R₃; (23) —SO₂R₄, wherein R₄ is from the groupconsisting of (a) alkyl, (b) aryl and (c) arylalkyl, wherein thealkylene group is of one to six carbon atoms; (24) —SO₂NR₅R₆, wherein R₅and R₆ are independently selected from the group consisting of (a)hydrogen, (b) alkyl, (c) aryl and (d) arylalkyl, wherein the alkylenegroup is of one to six carbon atoms; (25) —NR₇R₈, wherein R₇ and R₈ areindependently selected from the group consisting of (a) hydrogen; (b) anN-protecting group; (c) alkyl of one to six carbon atoms; (d) alkenyl oftwo to six carbon atoms; (e) alkynyl of two to six carbon atoms; (f)aryl; (g) arylalkyl, wherein the alkylene group is of one to six carbonatoms; (h) cycloalkyl of three to eight carbon atoms and (i)cycloalkylalkyl, wherein the cycloalkyl group is of three to eightcarbon atoms, and the alkylene group is of one to ten carbon atoms, withthe proviso that no two groups are bound to the nitrogen atom through acarbonyl group or a sulfonyl group.

The term “amino,” as used herein, represents an —NH₂ group.

The term “aminoalkyl,” as used herein, represents an alkyl group, asdefined herein, substituted by an amino group.

The term “aryl,” as used herein, represents a mono- or bicycliccarbocyclic ring system having one or two aromatic rings and isexemplified by phenyl, naphthyl, 1,2-dihydronaphthyl,1,2,3,4-tetrahydronaphthyl, fluorenyl, indanyl, indenyl and the like andmay be optionally substituted with one, two, three, four or fivesubstituents independently selected from the group consisting of (1)alkanoyl of one to six carbon atoms; (2) alkyl of one to six carbonatoms; (3) alkoxy of one to six carbon atoms; (4) alkoxyalkyl, whereinthe alkyl and alkylene groups are independently of one to six carbonatoms; (5) alkylsulfinyl of one to six carbon atoms; (6)alkylsulfinylalkyl, wherein the alkyl and alkylene groups areindependently of one to six carbon atoms; (7) alkylsulfonyl of one tosix carbon atoms; (8) alkylsulfonylalkyl, wherein the alkyl and alkylenegroups are independently of one to six carbon atoms; (9) aryl; (10)arylalkyl, wherein the alkyl group is of one to six carbon atoms; (11)amino; (12) aminoalkyl of one to six carbon atoms; (13) aryl; (14)arylalkyl, wherein the alkylene group is of one to six carbon atoms;(15) aryloyl; (16) azido; (17) azidoalkyl of one to six carbon atoms;(18) carboxaldehyde; (19) (carboxaldehyde)alkyl, wherein the alkylenegroup is of one to six carbon atoms; (20) cycloalkyl of three to eightcarbon atoms; (21) cycloalkylalkyl, wherein the cycloalkyl group is ofthree to eight carbon atoms and the alkylene group is of one to tencarbon atoms; (22) halo; (23) haloalkyl of one to six carbon atoms; (24)heterocycle; (25) (heterocycle)oxy; (26) (heterocycle)oyl; (27) hydroxy;(28) hydroxyalkyl of one to six carbon atoms; (29) nitro; (30)nitroalkyl of one to six carbon atoms; (31) N-protected amino; (32)N-protected aminoalkyl, wherein the alkylene group is of one to sixcarbon atoms; (33) oxo; (34) thioalkoxy of one to six carbon atoms; (35)thioalkoxyalkyl, wherein the alkyl and alkylene groups are independentlyof one to six carbon atoms; (36) —(CH₂)_(q)CO₂R₂, wherein q is zero tofour; (37) —(CH₂)_(q)C(O)NR₂R₃; (38) —(CH₂)_(q)SO₂R₄, wherein R₄ isselected from the group consisting of (a) alkyl, (b) aryl and (c)arylalkyl, wherein the alkylene group is of one to six carbon atoms;(39) —(CH₂)_(q)SO₂NR₅R₆, wherein R₅ and R₆ are independently selectedfrom the group consisting of (a) hydrogen, (b) alkyl, (c) aryl and (d)arylalkyl, wherein the alkylene group is of one to six carbon atoms;(40) —(CH₂)_(q)NR₇R₈, wherein R₇ and R₈ are independently selected fromthe group consisting of (a) hydrogen, (b) an N-protecting group, (c)alkyl of one to six carbon atoms, (d) alkenyl of two to six carbonatoms, (e) alkynyl of two to six carbon atoms, (f) aryl, (g) arylalkyl,wherein the alkylene group is of one to six carbon atoms, (h) cycloalkylof three to eight carbon atoms and (i) cycloalkylalkyl, wherein thecycloalkyl group is of three to eight carbon atoms, and the alkylenegroup is of one to ten carbon atoms, with the proviso that no two groupsare bound to the nitrogen atom through a carbonyl group or a sulfonylgroup; (41) oxo; (42) perfluoroalkyl; (43) perfluoroalkoxy; (44)aryloxy; (45) cycloalkoxy; (46) cycloalkylalkoxy; and (47) arylalkoxy.

The term “arylalkyl,” as used herein, represents an aryl group attachedto the parent molecular group through an alkyl group.

The term “arylalkoxy,” as used herein, represents an arylalkyl groupattached to the parent molecular group through an oxygen atom.

The term “aryloxy,” as used herein, represents an aryl group which isattached to the parent molecular group through an oxygen atom.

The term “aryloyl,” as used herein, represents an aryl group which isattached to the parent molecular group through a carbonyl group.

The term “azido,” as used herein, represents an —N₃ group.

The term “azidoalkyl,” as used herein, represents an alkyl group, asdefined herein, substituted by an azido group.

The term “carbonyl,” as used herein, represents a C═O group.

The term “carboxaldehyde,” as used herein, represents a —CHO group.

The term “(carboxaldehyde)alkyl,” as used herein, represents an alkylgroup, as defined herein, substituted by a carboxaldehyde group.

The term “carboxy,” as used herein, represents a —CO₂H group.

The term “carboxyalkyl,” as used herein, represents an alkyl group, asdefined herein, substituted by a carboxy group.

The term “cycloalkyl,” as used herein represents a monovalent saturatedcyclic hydrocarbon group and is exemplified by cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl, bicyclo[2.2.1.]heptyl and thelike. The cycloalkyl groups of this invention can be optionallysubstituted with (1) alkanoyl of one to six carbon atoms; (2) alkyl ofone to six carbon atoms; (3) alkoxy of one to six carbon atoms; (4)alkoxyalkyl, wherein the alkyl and alkylene groups are independently ofone to six carbon atoms; (5) alkylsulfinyl of one to six carbon atoms;(6) alkylsulfinylalkyl, wherein the alkyl and alkylene groups areindependently of one to six carbon atoms; (7) alkylsulfonyl of one tosix carbon atoms; (8) alkylsulfonylalkyl, wherein the alkyl and alkylenegroups are independently of one to six carbon atoms; (9) aryl; (10)arylalkyl, wherein the alkyl group is of one to six carbon atoms; (11)amino; (12) aminoalkyl of one to six carbon atoms; (13) aryl; (14)arylalkyl, wherein the alkylene group is of one to six carbon atoms;(15) aryloyl; (16) azido; (17) azidoalkyl of one to six carbon atoms;(18) carboxaldehyde; (19) (carboxaldehyde)alkyl, wherein the alkylenegroup is of one to six carbon atoms; (20) cycloalkyl of three to eightcarbon atoms; (21) cycloalkylalkyl, wherein the cycloalkyl group is ofthree to eight carbon atoms and the alkylene group is of one to tencarbon atoms; (22) halo; (23) haloalkyl of one to six carbon atoms; (24)heterocycle; (25) (heterocycle)oxy; (26) (heterocycle)oyl; (27) hydroxy;(28) hydroxyalkyl of one to six carbon atoms; (29) nitro; (30)nitroalkyl of one to six carbon atoms; (31) N-protected amino; (32)N-protected aminoalkyl, wherein the alkylene group is of one to sixcarbon atoms; (33) oxo; (34) thioalkoxy of one to six carbon atoms; (35)thioalkoxyalkyl, wherein the alkyl and alkylene groups are independentlyof one to six carbon atoms; (36) —(CH₂)_(q)CO₂R₂, wherein q is zero tofour; (37) —(CH₂)_(q)C(O)NR₂R3; (38) —(CH₂)_(q)SO₂R₄, wherein R₄ isselected from the group consisting of (a) alkyl, (b) aryl and (c)arylalkyl, wherein the alkylene group is of one to six carbon atoms;(39) —(CH₂)_(q)SO₂NR₅R₆, wherein R₅ and R₆ are independently selectedfrom the group consisting of (a) hydrogen, (b) alkyl, (c) aryl and (d)arylalkyl, wherein the alkylene group is of one to six carbon atoms;(40) —(CH₂)_(q)NR₇R₈, wherein R₇ and R₈ are independently selected fromthe group consisting of (a) hydrogen, (b) an N-protecting group, (c)alkyl of one to six carbon atoms, (d) alkenyl of two to six carbonatoms, (e) alkynyl of two to six carbon atoms, (f) aryl, (g) arylalkyl,wherein the alkylene group is of one to six carbon atoms, (h) cycloalkylof three to eight carbon atoms and (i) cycloalkylalkyl, wherein thecycloalkyl group is of three to eight carbon atoms, and the alkylenegroup is of one to ten carbon atoms, with the proviso that no two groupsare bound to the nitrogen atom through a carbonyl group or a sulfonylgroup; (41) oxo; (42) perfluoroalkyl; (43) perfluoroalkoxy; (44)aryloxy; (45) cycloalkoxy; (46) cycloalkylalkoxy; and (47) arylalkoxy.

The term “cycloalkenyl,” as used herein represents a monovalent cyclichydrocarbon having at least one carbon—carbon double bond. Thecycloalkenyl groups of this invention can be optionally substituted with(1) alkanoyl of one to six carbon atoms; (2) alkyl of one to six carbonatoms; (3) alkoxy of one to six carbon atoms; (4) alkoxyalkyl, whereindie alkyl and alkylene groups are independently of one to six carbonatoms; (5) alkylsulfinyl of one to six carbon atoms; (6)alkylsulfinylalkyl, wherein the alkyl and alkylene groups areindependently of one to six carbon atoms; (7) alkylsulfonyl of one tosix carbon atoms; (8) alkylsulfonylalkyl, wherein the alkyl and alkylenegroups are independently of one to six carbon atoms; (9) aryl; (10)arylalkyl, wherein the alkyl group is of one to six carbon atoms; (11)amino; (12) aminoalkyl of one to six carbon atoms; (13) aryl; (14)arylalkyl, wherein the alkylene group is of one to six carbon atoms;(15) aryloyl; (16) azido; (17) azidoalkyl of one to six carbon atoms;(18) carboxaldehyde; (19) (carboxaldehyde)alkyl, wherein the alkylenegroup is of one to six carbon atoms; (20) cycloalkyl of three to eightcarbon atoms; (21) cycloalkylalkyl, wherein the cycloalkyl group is ofthree to eight carbon atoms and the alkylene group is of one to tencarbon atoms; (22) halo; (23) haloalkyl of one to six carbon atoms; (24)heterocycle; (25) (heterocycle)oxy; (26) (heterocycle)oyl; (27) hydroxy;(28) hydroxyalkyl of one to six carbon atoms; (29) nitro; (30)nitroalkyl of one to six carbon atoms; (31) N-protected amino; (32)N-protected aminoalkyl, wherein the alkylene group is of one to sixcarbon atoms; (33) oxo; (34) thioalkoxy of one to six carbon atoms; (35)thioalkoxyalkyl, wherein the alkyl and alkylene groups are independentlyof one to six carbon atoms; (36) —(CH₂)_(q)CO₂R₂, wherein q is zero tofour; (37) —(CH₂)_(q)C(O)NR₂R₃; (38) —(CH₂)_(q)SO₂R₄, wherein R₄ isselected from the group consisting of (a) alkyl, (b) aryl and (c)arylalkyl, wherein the alkylene group is of one to six carbon atoms;(39) —(CH₂)_(q)SO₂NR₅R₆, wherein R₅ and R₆ are independently selectedfrom the group consisting of (a) hydrogen, (b) alkyl, (c) aryl and (d)arylalkyl, wherein the alkylene group is of one to six carbon atoms;(40) —(CH₂)_(q)NR₇R₈, wherein R₇ and R₈ are independently selected fromthe group consisting of (a) hydrogen, (b) an N-protecting group, (c)alkyl of one to six carbon atoms, (d) alkenyl of two to six carbonatoms, (e) alkynyl of two to six carbon atoms, (f) aryl, (g) arylalkyl,wherein the alkylene group is of one to six carbon atoms, (h) cycloalkylof three to eight carbon atoms and (i) cycloalkylalkyl, wherein thecycloalkyl group is of three to eight carbon atoms, and the alkylenegroup is of one to ten carbon atoms, with the proviso that no two groupsare bound to the nitrogen atom through a carbonyl group or a sulfonylgroup; (41) oxo; (42) perfluoroalkyl; (43) perfluoroalkoxy; (44)aryloxy; (45) cycloalkoxy; (46) cycloalkylalkoxy; and (47) arylalkoxy.

The term “cycloalkoxy,” as used herein represents a cycloalkyl group, asdefined herein, attached to the parent molecular group through an oxygenatom.

The term “cycloalkylalkoxy,” as used herein, represents an alkoxy group,as defined herein, to which is attached a cycloalkyl group.

The term “cycloalkylalkyl,” as used herein, represents a cycloalkylgroup, as defined herein, attached to the parent molecular group throughan alkyl group.

The term “haloalkyl,” as used herein, represents an alkyl group, asdefined herein, substituted by one, two, or three halogen atoms and isexemplified by chloromethyl, bromoethyl, trifluoromethyl and the like.

The term “halogen,” as used herein, represents F, Cl, Br and I.

The term “heterocycle,” as used herein, represents a 5-, 6- or7-membered ring containing one, two or three heteroatoms independentlyselected from the group consisting of nitrogen, oxygen and sulfur. The5-membered ring has zero to two double bonds and the 6- and 7-memberedrings have zero to three double bonds. The term “heterocycle” alsoincludes bicyclic, tricyclic and tetracyclic groups in which any of theabove heterocyclic rings is fused to one or two rings independentlyselected from the group consisting of an aryl ring, a cyclohexane ring,a cyclohexene ring, a cyclopentane ring, a cyclopentene ring and anothermonocyclic heterocyclic ring such as indolyl, quinolyl, isoquinolyl,tetrahydroquinolyl, benzofuryl, benzothienyl and the like. Heterocyclicsinclude pyrrolyl, pyrrolinyl, pyrrolidinyl, pyrazolyl, pyrazolinyl,pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyridyl,piperidinyl, homopiperidinyl, pyrazinyl, piperazinyl, pyrimidinyl,pyridazinyl, oxazolyl, oxazolidinyl, isoxazolyl, isoxazolidiniyl,morpholinyl, thiomorpholinyl, thiazolyl, thiazolidinyl, isothiazolyl,isothiazolidinyl, indolyl, quinolinyl, isoquinolinyl, benzimidazolyl,benzothiazolyl, benzoxazolyl, furyl, thienyl, thiazolidinyl,isothiazolyl, isoindazoyl, triazolyl, tetrazolyl, oxadiazolyl, uricyl,thiadiazolyl, pyrimidyl, tetrahydrofuranyl, dihydrofuranyl,tetrahydrothienyl, dihydrothienyl, dihydroinidolyl, tetrahydroquinolyl,tetrahydroisoquinolyl, pyranyl, dihydropyranyl, dithiazolyl,benzofuranyl, benzothienyl and the like. Heterocyclic groups alsoinclude compounds of the formula

wherein F is selected from the group consisting of —CH₂—, —CH₂O— and—O—, and G is selected from the group consisting of —C(O)— and—(C(R′)(R″))_(v)—, wherein R′ and R″ are independently selected from thegroup consisting of hydrogen or alkyl of one to four carbon atoms, and vis one to three and includes groups such as 1,3-benzodioxolyl,1,4-benzodioxanyl and the like. Any of the heterocycle groups mentionedherein may be optionally substituted with one, two, three, four or fivesubstituents independently selected from the group consisting of (1)alkanoyl of one to six carbon atoms; (2) alkyl of one to six carbonatoms; (3) alkoxy of one to six carbon atoms; (4) alkoxyalkyl, whereinthe alkyl and alkylene groups are independently of one to six carbonatoms; (5) alkylsulfinyl of one to six carbon atoms; (6)alkylsulfinylalkyl, wherein the alkyl and alkylene groups areindependently of one to six carbon atoms; (7) alkylsulfonyl of one tosix carbon atoms; (8) alkylsulfonylalkyl, wherein the alkyl and alkylenegroups are independently of one to six carbon atoms; (9) aryl; (10)arylalkyl, wherein the alkyl group is of one to six carbon atoms; (11)amino; (12) aminoalkyl of one to six carbon atoms; (13) aryl; (14)arylalkyl, wherein the alkylene group is of one to six carbon atoms;(15) aryloyl; (16) azido; (17) azidoalkyl of one to six carbon atoms;(18) carboxaldehyde; (19) (carboxaldehyde)alkyl, wherein the alkylenegroup is of one to six carbon atoms; (20) cycloalkyl of three to eightcarbon atoms; (21) cycloalkylalkyl, wherein the cycloalkyl group is ofthree to eight carbon atoms and the alkylene group is of one to tencarbon atoms; (22) halo; (23) haloalkyl of one to six carbon atoms; (24)heterocycle; (25) (heterocycle)oxy; (26) (heterocycle)oyl; (27) hydroxy;(28) hydroxyalkyl of one to six carbon atoms; (29) nitro; (30)nitroalkyl of one to six carbon atoms; (31) N-protected amino; (32)N-protected aminoalkyl, wherein the alkylene group is of one to sixcarbon atoms; (33) oxo; (34) thioalkoxy of one to six carbon atoms; (35)thioalkoxyalkyl, wherein the alkyl and alkylene groups are independentlyof one to six carbon atoms; (36) —(CH₂)_(q)CO₂R₂, wherein q is zero tofour; (37) —(CH₂)_(q)C(O)NR₂R₃; (38) —(CH₂)_(q)SO₂R₄, wherein R₄ isselected from the group consisting of (a) alkyl, (b) aryl and (c)arylalkyl, wherein the alkylene group is of one to six carbon atoms;(39) —(CH₂)_(q)SO₂NR₅R₆, wherein R₅ and R₆ are independently selectedfrom the group consisting of (a) hydrogen, (b) alkyl, (c) aryl and (d)arylalkyl, wherein the alkylene group is of one to six carbon atoms;(40) —(CH₂)_(q)NR₇R₈, wherein R₇ and R₈ are independently selected fromthe group consisting of (a) hydrogen, (b) an N-protecting group, (c)alkyl of one to six carbon atoms, (d) alkenyl of two to six carbonatoms, (e) alkynyl of two to six carbon atoms, (f) aryl, (g) arylalkyl,wherein the alkylene group is of one to six carbon atoms, (h) cycloalkylof three to eight carbon atoms and (i) cycloalkylalkyl, wherein thecycloalkyl group is of three to eight carbon atoms, and the alkylenegroup is of one to ten carbon atoms, with the proviso that no two groupsare bound to the nitrogen atom through a carbonyl group or a sulfonylgroup; (41) oxo; (42) perfluoroalkyl; (43) perfluoroalkoxy; (44)aryloxy; (45) cycloalkoxy; (46) cycloalkylalkoxy; and (47) arylalkoxy.

The term “(heterocycle)oxy,” as used herein, represents a heterocyclegroup, as defined herein, attached to the parent molecular group throughoxygen.

The term “(heterocycle)oyl,” as used herein, represents a heterocyclegroup, as defined herein, attached to the parent molecular group througha carbonyl group.

The term “hydroxy” as used herein, represents an —OH group.

The term “hydroxyalkyl,” as used herein, represents an alkyl group, asdefined herein, substituted by one to three hydroxy groups, with theproviso that no more than one hydroxy group may be attached to a singlecarbon atom of the alkyl group and is exemplified by hydroxymethyl,dihydroxypropyl and the like.

The term “methine” as used herein, represents a ═C(H)— group.

The term “N-protected amino,” as used herein, refers to an amino group,as defined herein, to which is attached an N-protecting ornitrogen-protecting group, as defined herein.

The term “N-protected aminoalkyl,” as used herein, refers to an alkylgroup, as defined herein, which is substituted by an N-protecting ornitrogen-protecting group, as defined herein.

The term “nitro,” as used herein, represents an —NO₂ group.

The term “nitroalkyl,” as used herein, represents an alkyl groupsubstituted by an —NO₂ group.

The terms “N-protecting group” or “nitrogen protecting group” as usedherein, represent those groups intended to protect an amino groupagainst undersirable reactions during synthetic procedures. Commonlyused N-protecting groups are disclosed in Greene, “Protective Groups InOrganic Synthesis,” (John Wiley & Sons, New York (1981)), which isincorporated herein by reference. N-protecting groups comprise acylgroups such as formyl, acetyl, propionyl, pivaloyl, t-butylacetyl,2-chloroacetyl, 2-bromoacetyl, trifluoroacetyl, trichloroacetyl,phthalyl, o-nitrophenoxyacetyl, α-chlorobutyryl, benzoyl,4-chlorobenzoyl, 4-bromobenzoyl, 4-nitrobenzoyl and chiral auxiliariessuch as protected or unprotected D, L or D, L-amino acids such asalanine, leucine, phenylalanine and the like; sulfonyl groups such asbenzenesulfonyl, p-toluenesulfonyl and the like; carbamate forminggroups such as benzyloxycarbonyl, p-chlorobenzyloxycarbonyl,p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl,2-nitrobenzyloxycarbonyl, p-bromobenizyloxycarbonyl,3,4-dimethoxybenzyloxycarbonyl, 3,5-dimethoxybenzyloxycarbonyl,2,4-dimethoxybenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl,2-nitro-4,5-dimethoxybenzyloxycarbonyl,3,4,5-trimethoxybenzyloxycarbonyl,1-(p-biphenylyl)-1-methylethoxycarbonyl,α,α-dimethyl-3,5-dimethoxybenzyloxycarbonyl, benzhydryloxycarbonyl,t-butyloxycarbonyl, diisopropylmethoxycarbonyl, isopropyloxycarbonyl,ethoxycarbonyl, methoxycarbonyl, allyloxycarbonyl,2,2,2,-trichloroethoxycarbonyl, phenoxycarbonyl, 4-nitrophenoxycarbonyl, fluorenyl-9-methoxycarbonyl, cyclopentyloxycarbonyl,adamantyloxycarbonyl, cyclohexyloxycarbonyl, phenylthiocarbonyl and thelike, arylalkyl groups such as benzyl, triphenylmethyl, benzyloxymethyland the like and silyl groups such as trimethylsilyl and the like.Preferred N-protecting groups are formyl, acetyl, benzoyl, pivaloyl,t-butylacetyl, alanyl, phenylsulfonyl, benzyl, t-butyloxycarbonyl (Boc)and benzyloxycarbonyl (Cbz).

The term “oxo,” as used herein, represents ═O.

The term “perfluoroalkyl,” as used herein, represents an alkyl group, asdefined herein, wherein each hydrogen radical bound to the alkyl grouphas been replaced by a fluoride radical. Perfluoroalkyl groups areexemplified by trifluoromethyl, pentafluoroethyl, and the like.

The term “perfluoroalkoxy,” as used herein, refers to a perfluoroalkylgroup, as defined herein, attached to the parent molecular group throughan oxygen atom.

The term “pharmaceutically acceptable salt,” as use herein, representsthose salts which are, within the scope of sound medical judgement,suitable for use in contact with the tissues of humans and lower animalswithout undue toxicity, irritation, allergic response and the like andare commensurate with a reasonable benefit/risk ratio. Pharmaceuticallyacceptable salts are well known in the art. For example, S. M Berge, etal. describe pharmaceutically acceptable salts in detail in J.Pharmaceutical Sciences, 1977, 66:1-19. The salts can be prepared insitu during the final isolation and purification of the compounds of theinvention or separately by reacting the free base group with a suitableorganic acid. Representative acid addition salts include acetate,adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate,bisulfate, borate, butyrate, camphorate, camphersulfonate, citrate,cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate,fumarate, glucoheptonate, glycerophosphate, hemisulfate, heptonate,hexanoate, hydrobromide, hydrochloride, hydroiodide,2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, laurylsulfate, malate, maleate, malonate, methanesulfonate,2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate,pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate,pivalate, propionate, stearate, succinate, sulfate, tartrate,thiocyanate, toluenesulfonate, undecanoate, valerate salts and the like.Representative alkali or alkaline earth metal salts include sodium,lithium, potassium, calcium, magnesium and the like, as well as nontoxicammonium, quaternary ammonium, and amine cations, including, but notlimited to ammonium, tetramethylammonium, tetraethylammonium,methylamine, dimethylamine, trimethylamine, triethylamine, ethylamineand the like. The term “pharmaceutically acceptable ester,” as usedherein, represents esters which hydrolyze in vivo and include those thatbreak down readily in the human body to leave the parent compound or asalt thereof. Suitable ester groups include, for example, those derivedfrom pharmaceutically acceptable aliphatic carboxylic acids,particularly alkanoic, alkenoic, cycloalkanoic and alkanedioic acids, inwhich each alkyl or alkenyl group preferably has not more than 6 carbonatoms. Examples of particular esters includes formates, acetates,propionates, butyates, acrylates and ethylsuccinates.

The term “pharmaceutically acceptable prodrugs” as used herein,represents those prodrugs of the compounds of the present inventionwhich are, within the scope of sound medical judgement, suitable for usein contact with with the tissues of humans and lower animals with unduetoxicity, irritation, allergic response, and the like, commensurate witha reasonable benefit/risk ratio, and effective for their intended use,as well as the zwitterionic forms, where possible, of the compounds ofthe invention.

The term “prodrug,” as used herein, represents compounds which arerapidly transformed in vivo to the parent compound of the above formula,for example, by hydrolysis in blood. A thorough discussion is providedin T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol.14 of the A.C.S. Symposium Series, Edward B. Roche, ed., BioreversibleCarriers in Drug Design, American Pharmaceutical Association andPergamon Press, 1987, and Judkins, et al. Synthetic Communications,26(23), 4351-4367 (1996), each of which is incorporated herein byreference.

The term “spiroalkyl,” as used herein, represents an alkylene diradical,both ends of which are bonded to the same carbon atom of the parentgroup to form a spirocyclic group.

The term “sulfonyl,” as used herein, represents an —SO₂— group.

The term “thioalkoxy,” as used herein, represents represents an alkylgroup attached to the parent molecular group through a sulfur atom.

The term “thioalkoxyalkyl,” as used herein, represents an alkyl groupsubstituted by a thioalkoxy group.

Asymmetric or chiral centers may exist in the compounds of the presentinvention. The present invention contemplates the various stercoisomersand mixtures thereof. Individual stereoisomers of compounds or thepresent invention are prepared synthetically from commercially availablestarting materials which contain asymmetric or chiral centers or bypreparation of mixtures of enantiometic compounds followed by resolutionwell-known to those of ordinary skill in the art. These methods ofresolution are exemplified by (1) attachment of a racemic mixture ofenantiomers, designated (±), to a chiral auxiliary, separation of theresulting diastereomers by recrystallization or chromatography andliberation of the optically pure product from the auxiliary or (2)direct separation of the mixture of optical enantiomers on chiralchromatographic columns. Enantiomers are designated herein by thesymbols “R” or “S,” depending on the configuration of subsitiuentsaround the chiral carbon atom.

Geometric isomers may also exist in the compounds of the presentinvention. The present invention contemplates the various geometricisomers and mixtures thereof resulting from the arrangement ofsubstituents around a carbon—carbon double bond and designates suchisomers as of the Z or E configuration, wherein the term “Z” representssubstituents on the same side of the carbon—carbon double bond and theterm “E” represents substituents on opposite sides of the carbon—carbondouble bond.

PREFERRED EMBODIMENTS

Preferred compounds of the present invention have formula (I), wherein

A and C are hydrogen and

B is —L_(B)R_(B), wherein

—L_(B)— is —O—, and

R_(B) is alkyl of two to six carbon atoms, and

wherein the alkyl group is substituted.

More preferred embodiments of the present invention have formula (I),wherein

A is —L_(A)R_(A) and

B and C are hydrogen,

wherein —L_(A)— is selected from the group consisting of

(1) a covalent bond,

(2) —(CH₂)_(m)—,

(3) —NR₂C(X)—,

(4) —C(X)NR₂—,

(5) —NR₂C(X)NR₃—,

(6) —C≡C—,

(7) —CH═CH—,

(8) —C(X)NR₂(CH₂)_(n)C≡C—

(9) —C(X)—,

(10) —O—,

(11) —OC(O)NR₂— and

(12)

 and wherein

R_(A) is selected from the group consisting of

(1) amino;

(2) aryl;

(3) alkyl of one to ten carbon atoms;

(4) arylalkyl, wherein the alkylene group is of one to ten carbon atoms;

(5) cycloalkyl of three to eight carbon atoms;

(6) arylalkoxy, wherein the alkylene group is of one to ten carbon atomsand

(7) heterocycle, wherein the heterocycle is selected from the groupconsisting of

(1) furanyl,

(2) thienyl and

(3) imidazolyl; and

wherein, at each occurence, R₂ is selected from the group consisting of

 (1) hydrogen and

 (2) alkyl of one to six carbon atoms; and

wherein, at each occurence,

 m is two,

 n is one,

 R₁ and R₃ are hydrogen,

 W and X are O,

 aryl is phenyl,

 the alkyl group and the aryl group are optionally substituted and

 the alkenyl group is substituted.

Still more preferred compounds of the present invention have formula(I), wherein

A and B are hydrogen;

C is —L_(C)R_(C);

—L_(C)— is selected from the group consisting of

(1) a covalent bond,

(2) —OC(O)NR₂—,

(3) —SO₂NR₂—,

(4) —C(X)NR₂—,

(5) —NR₁— and

(6) —O—;

R_(C) is selected from the group consisting of

(1) alkyl of one to six carbon atoms;

(2) aryl;

(3) arylalkyl, wherein the alkylene group is of one to six carbon atomsand

(4) hererocycle, wherein the heterocycle is selected from the groupconsisting of

(1) furanyl;

(2) pyrimidinyl; and

(3)

wherein F is —O—, G is —(C(R′)(R″))_(v)—, R′ and R″ are hydrogen and vis one;

X is O; and

wherein, at each occurence,

 R₁ and R₂ are H,

 aryl is phenyl and

 the alkyl is optionally substituted.

Still more preferred compounds of the present invention have formula (I)wherein

A is —L_(A)R_(A),

B is —L_(B)R_(B),

C is hydrogen,

—L_(A)— and —L_(B)— are —O—, and

R_(A) and R_(B) are alkyl of one to six carbon atoms.

Still more preferred compounds of the present invention have formula (I)wherein

A is —L_(A)R_(A),

B is —L_(B)R_(B),

C is —L_(C)R_(C),

—L_(A)—, —L_(B)—, and —L_(C)— are —O— and

R_(A), R_(B), and R_(C) are alkyl of one to six carbon atoms.

Still more preferred compounds of the present invention have formula (I)wherein

A is hydrogen;

B is —L_(B)R_(B);

C is —L_(C)R_(C);

—L_(B)— is —O—;

—L_(C)— is selected from the group consisting of

(1) a covalent bond,

(2) —O—,

(3) —CH═CH—,

(4) —NR₁— and

(5) —NR₂C(O)O—;

R_(B) is selected from the group consisting of

(1) alkyl and

(2) arylalkyl, wherein the alkylene group is of one to six carbon atoms;

R_(C) is selected from the group consisting of

(1) alkyl of one to six carbon atoms;

(2) alkenyl of one to six carbon atoms;

(3) halogen;

(4) aryl and

(5) heterocycle, wherein

the heterocycle is selected from the group consisting of

(1) benzofuranyl;

(2) tetrahydrofuranyl;

(3) pyrimidinyl;

(4) pyrazolyl;

(5) furanyl;

(6) pyrimidinyl;

(7) thiazolyl and

(8)

wherein F is —O—, G is —(C(R′)(R″))_(v)—, R′ and R″ are hydrogen and vis one; and

wherein, at each occurence,

aryl is phenyl and

alkyl, aryl and heterocycle are optionally substituted.

Preferred compounds falling within the scope of formula (I) include:

7,8-dimethoxy-2-naphthalenecarboximidamide mono(trifluoroacetate) salt;

6,7,8-trimethoxy-2-naphthalenecarboximidamide mono(trifluoroacetate)salt;

6,7-dimethoxy-2-naphthalenecarboximidamide mono(trifluoroacetate) salt;

2-[(7-aminoiminomethyl-2-methoxy-1-naphthalenyl)oxy]acetamidemono(trifluoroacetate) salt;

7-benzyloxy-8-iodo-2-naphthalenecarboximidamide mono(trifluoroacetate)salt;

methyl [(7-aminoiminomethyl-2-methoxy-1-naphthalenyl)oxy]acetatemono(trifluoroacetate) salt;

2-[(7-aminoiminomethyl-2-methoxy-1-naphthalenyl)oxy]-yl-acetic acidmono(trifluoroacetate) salt;

N-[4-(aminomethyl)phenyl]-6-aminoiminomethyl-2-naphthalenecarboxamidebis(trifluoroacetate) salt;

N-[4-(amino)phenyl]-6-aminoiminomethyl-2-naphthalenecarboxamidebis(trifluoroacetate) salt;

1-[(7-aminoiminomethyl-2-methoxy-1-naphthalenyl)oxy]-3-hydroxypropanemono(trifluoroacetate) salt;

phenylmethyl [7-(aminoiminomethyl)-1-naphthalenyl)carbamatemono(trifluoroacetate) salt;

N-[7-(aminoiminomethyl)-1-naphthalenyl)acetamide mono(trifluoroacetate)salt;

methyl [7-(aminoiminomethyl)-1-naphthalenyl)carbamatemono(trifluoroacetate) salt;

methyl 3-[[7-(aminoiminomethyl)-1-naphthalenyl]amino]-3-oxopropanoatemono(trifluoroacetate) salt;

N-[7-(aminoiminomethyl)-1-naphthalenyl]-2-(phenylmethoxy)acetamidemono(trifluoroacetate) salt;

N-[7-(aminoiminomethyl)-1-naphthalenyl]-1,3-benzodioxole-5-carboxamidemono(trifluoroacetate) salt;

N-[7-(aminoiminomethyl)-1-naphthalenyl]benzemethanesulfonamidemono(trifluoroacetate) salt;

1-[(7-aminoiminomethyl-2-methoxy-1-naphthalenyl)oxy]-3-bromopropanemono(hydrochloride) salt;

3-[(7-aminoiminomethyl-2-methoxy-1-naphthalenyl)oxy]propenemono(trifluoroacetate) salt;

1-[(7-aminoiminomethyl-2-methoxy-1-naphthalenyl)oxy]-3-phenylpropanemono(hydrochloride) salt;

1-[(7-aminoiminomethyl-2-methoxy-1-naphthalenyl)oxy]-3-[1-(3,4-dimethoxy)phenyl]-propanemono(hydrochloride) salt;

7-methoxy-8-(2-furanyl)-2-naphthalenecarboximidamidemono(trifluoroacetate) salt;

methyl6-(aminoiminomethyl)-4-[(methoxycarbonyl)amino]-2-naphthalenecarboxylatemono(trifluoroacetate) salt;

(E)-(7-methoxy-8-[2-(Phenyl)ethenyl])-2-naphthaleneimidamidemono(trifluoroacetate) salt

6-(4-phenylbutynyl)-2-naphthalenecarboximidamide mono(trifluoroacetate)salt;

7-(2-hydroxyethoxy)-8-iodo-2-naphthalenecarboximidamidemono(trifluoroacetate) salt;

7-(2-hydroxyethoxy)-2-naphthalenecarboximidamide mono(trifluoroacetate)salt;

6-(4-methyl-1-pentynyl)-2-naphthalenecarboximidamidemono(trifluoroacetate) salt;

6-(5-phenylpentynyl)-2-naphtlialenecaiboximidamidemono(trifluoroacetate) salt;

6-(3-phenyl-1-propyilyl)-2-naphthalenecarboximidamidemono(trifluoroacetate) salt;

6-(phenylethynyl)-2-naphthalenecarboximidamide mono(trifluoroacetate)salt;

3-amino-N-[3-[6-(aminoiminomethyl)-2-naphthalenyl]-2-propynyl]benzamidemono(trifluoroacetate) salt;

4-amino-N-[3-(6-aminoiminomethyl-2-naphthalenyl)-2-propynyl]benzamidemono(trifluoroacetate) salt;

(S)-2-amino-N-[1-[(6-aminoiminomethyl-2-naphthalenyl)carbonyl]cyclohexyl]propionamidebis(trifluoroacetate) salt;

6-methoxy-8-benzyloxy-2-naphthalenecarboximidamidemono(trifluoroacetate) salt;

2-[(7-aminoiminomethyl-3-methoxy-1-naphthalenyl)oxy]acetamidemono(trifluoroacetate) salt;

N-(6-aminoiminomethyl-2-naphthalenyl)-N′-phenylureamono(trifluoroacetate) salt;

(E)-6-[2-(phenyl)ethenyl]-2-naphthalenecarboximidamidemono(trifluoroacetate) salt;

6-[2-(phenyl)ethyl]-2-naphthalenecarboximidamide mono(trifluoroacetate)salt;

7-propoxy-8-iodo-2-naphthalenecarboximidamide mono(trifluoroacetate)salt;

(±)-6-(3-phenyloxiranyl)-2-naphthalenecarboximidamidemono(trifluoroacetate) salt;

(E)-6-[2-(2-thienyl)ethenyl]-2-naphthalenecarboximidamidemono(trifluoroacetate) salt;

6-(3-oxobutyl)-2-naphthalenecarboximidamide mono(trifluoroacetate) salt;

6-(3-methoxyphenyl)-2-naphthalenecarboximidamide mono(trifluoroacetate)salt;

N-[3-(methyl)phenyl]-6-aminoiminomethyl-2-napthalenecarboxamidemono(trifluoroacetate) salt;

6-(2-formylphenoxy)-2-naphthalenecarboximidamide mono(trifluoroacetate)salt;

6-(2-formylphenyl)-2-naphthalenecarboximidamide mono(trifluoroacetate)salt;

6-[2-(hydroxymethyl)phenyl]-2-naphthalenecarboximidamidemono(trifluoroacetate) salt;

6-(3-oxo-1-butenyl)-2-naphthalenecarboximidamide mono(trifluoroacetate)salt;

7-methoxy-8-(1H-pyrazol-4-yl)-2-naphthalenecarboximidamidemono(trifluoroacetate) salt;

7-methoxy-8-iodo-2-naphthalenecarboximidamide mono(trifluoroacetate)salt;

N-phenyl-6-aminoiminomethyl-2-naphthalenecarboxamidemono(methanesulfonate) salt;

4-[(6-aminoiminomethyl-2-naphthalenyl)oxy]-N-methlylbenzeneacetamidemono(trifluoroacetate) salt;

6-[2-(methylthio)phenyl]-2-naphthalenecarboximidamidemono(methanesulfonate) salt;

6-[2-(2-thiomethoxoxyethyl)phenyl]naphthalene-2-carboximidamidemono(methanesulfonate) salt;

7-methoxy-8-(3-furanyl)-2-naphthalenecarboximidamidemono(methanesulfonate) salt;

7-methoxy-8-(2-benzofuranyl)naphthalene-2-carboximidamidemono(methanesulfonate) salt;

(E)-8-[2-(1,3-benzodioxol-5-yl)ethenyl]-2-naphthalenecarboximidamidemono(methanesulfonate) salt;

(±)-7-methoxy-8-(tetrahydro-3-furanyl)-2-naphthalenecarboximidamidemono(methanesulfonate) salt;

6-[[4-(2-aminoethyl)phenyl]ethynyl]-2-naphthalenecarboximidamidemono(trifluoroacetate) salt;

7-methoxy-8-[2-pyrimidinyl(oxy)]-2-naphthalenecarboximidamidemono(trifluoroacetate) salt;

7-methoxy-8-[2-thiazoyl(oxy)]naphthalene-2-carboximidamidemono(trifluoroacetate) salt;

7-methoxy-8-(4-nitrophenoxy)-2-naphthalenecarboximidamidemono(trifluoroacetate) salt;

7-methoxy-8-pentafluorophenoxy-2-naphthalenecarboximidamidemono(trifluoroacetate) salt;

7-methoxy-8-[N-2-pyrimidinyl(amino)]-2-naphthalenecarboximidamidemono(trifluoroacetate) salt;

N-(6-aminoiminomethyl-2-naphthalenyl)-N′-benzylureamono(trifluoroacetate) salt;

N-(6-aminoiminomethyl-2-naphthalenyl)-N′-methylureamono(trifluoroacetate) salt;

N-(6-aminoiminomethyl-2-naphthalenyl)-N′-isopropylureamono(trifluoroacetate) salt;

N-(6-aminoiminomethyl-2-naphthalenyl)-N′-phenyl-N′-methylureamono(trifluoroacetate) salt;

6-aminonaphthalene-2-carboximidamide mono(trifluoroacetate) salt;

N-(6-aminoiminomethyl-2-naphthalenyl)-N′-cyclohexylureamono(trifluoroacetate) salt;

N-(6-aminoiminomethyl-2-naphthalenyl)-N′-benzyloxyureamono(trifluoroacetate) salt;

1,1-dimethylethyl[4-[[(6-cyano-2-naphthalenyl)amino]carbonyl]phenyl]carbamatemono(trifluoroacetate) salt

N-[6-(aminoiminomethyl)-2-naphthalenyl]-4-(aminomethyl)benzamidemono(trifluoroacetate) salt;

ethyl [6-(aminoiminomethyl)-2-naphthalenyl]carbamatemono(trifluoroacetate) salt;

1,1-dimethylethyl[4-[[[6-aminoiminomethyl)-2-naphthalenyl)amino]carbonyl]amino]phenyl]carbamate mono(trifluoroacetate) salt;

(E)-6-[2-(phenylthio)ethenyl]-2-naphthalenecarboximidamide mono(trifluoroacetate) salt;

(E)-6-[2-(2-furanyl)ethenyl]-2-naphthalenecarboximidamidemono(trifluoroacetate) salt;

(E)-6-[2-(1H-imidazol-1-yl)ethenyl]-2-naphthlalenecarboximidamidemono(trifluoroacetate) salt;

(E)-4-[2-(6-aminoiminomethyl-2-naphthalenyl)ethenyl]benzenesulfonamidemono(trifluoroacetate) salt;

(E)-4-[2-(6-aminoiminomethyl-2-naphthalenyl)ethenyl]benzoic acidmono(trifluoroacetate) salt;

4-[7-(aminoiminomethyl)-2-methoxy-1-naphthalenyl]dihydro-2(3H)-furanonemono(trifluoroacetate) salt;

7-methoxy-8-(1-acetyl-1H-pyrazolyl)-2-naphthalenecarboximidamidemono(trifluoroacetate) salt;

7-methoxy-8-[1-(methylsulfonyl)-1H-4-pyrazolyl]-2-naphthalenecarboximidamidemono(trifluoroacetate) salt;

(E)-4-[2-(6-aminoininomethyl-2-naphthalenyl)ethenyl]benzamidemono(trifluoroacetate) salt;

6-[2-(4-aminophenyl)ethoxy]-2-naphthalenecarboximidamidemono(trifluoroacetate) salt;

methyl [3-methoxy-6-(aminoiminomethyl)-4-naphthalenyl]carbamatemono(trifluoroacetate) salt;

7-methoxy-8-[2-pyrimidinyl(amino)]-2-naphthalenecarboximidamidebis(trifluoroacetate) salt;

fhthalenecarboxamide, mono(trifluoroacetate) salt;

6-(4-aminophenyl)-2-naphthalenecarboximidamide, bis(trifluoroacetate)salt;

methyl2-[4-[[[6-(aminoiminomethyl)-2-naphthalenyl]carbonyl]amino]-phenoxy]acetate,mono(trifluoroacetate)salt;

(E)-6-[2-[(3-hydroxymethyl)phenyl]ethenyl]-2-naphthalenecarboximidamide,mono(trifluoroacetate) salt;

6-(2-phenyl-1-cyclopropyl)-2-naphthalenecarboximidamide,mono(trifluoroacetate) salt;

(E)-6-[2-[4-(aminomethyl)phenyl]ethenyl]-2-naphthalenecarboximidamide,bis(trifluoroacetate) salt;

(E)-6-[2-[4-(1,2-dihdyroxyethyl)phenyl]ethenyl]-2-naphthalenecarboximidamide,mono(trifluoroacetate) salt;

(E)-6-[2-[4-(1R-amino-2-hydroxyethyl)phenyl]ethenyl]-2-naphthalenecarboximidamide,bis(trifluoroacetate) salt;

7-methoxy-8-(2-pyrimidinylamino)-2-naphthalenecarboximidamide,bis(trifluoroacetate) salt;

(E)-6-[2-[[4-(dimethylamino)methyl]phenyl]ethenyl]-2-naphthalenecarboximidamide,bis(trifluoroacetate) salt;

(E)-6-[2-[4-(hydroxymethyl)phenyl]ethenyl]-2-naphthalenecarboximidamide,mono(trifluoroacetate) salt;

4-[[6-(aminoiminomethyl)-2-naphthalenyl]ethynyl]-L-phenylalanine,mono(trifluoroacetate) salt;

6-(3-formylphenyl)-2-naphthalenecarboximidamide, mono(trifluoroacetate)salt;

(E)-6-[2-(1,2,3,4-tetrahydro-6-isoquinolinyl)ethenyl]-2-naphthalenecarboximidamide,bis(trifluoroacetate) salt;

(E)-6-[2-[3-(2-hydroxyethyl)phenyl]ethenyl]-2-naphthalenecarboximidamide,mono(trifluoroacetate) salt;

6-(aminoiminomethyl)-N-(2,3-dihydro-1H-inden-5-yl)-2-naphthalenecarboxamide,mono(trifluoroacetate) salt;

6-[(4-aminophenyl)ethynyl]-2-naphthalenecarboximidamide,bis(trifluoroacetate) salt;

1,1-dimethylethyl[2-[3-[[6-(aminoiminomethyl)-2-naphthalenyl]ethynyl]-6-methoxyphenyl]ethyl]carbamate,mono (trifluoroacetate) salt;

1,1-dimethylethyl[[4-[[6-(aminoiminomethyl)-2-naphathalenyl]ethynyl]-phenyl]methyl]carbamate,mono(trifluoroacetate) salt;

6-[[4-(aminomethyl)phenyl]ethynyl]-2-naphthalenecarboximidamide,bis(trifluoroacetate) salt;

6-[[3-(2-aminoethyl)-4-methoxyphenyl]ethynyl]-2-naphthalenecarboximidamide,bis(trifluoroacetate) salt;

6-[[4-(hydroxymethyl)phenyl]ethynyl]-2-naphthalenecarboximidamide,mono(trifluoroacetate) salt;

6-[(1,2,3,4-tetrahydro-6-isoquinolinyl)ethynyl]-2-naphthalenecarboximidamide,bis(trifluoroacetate) salt;

6-(aminoiminomethyl)-N-(4-methylphenyl)-2-naphthalenecarboxamide,mono(trifluoroacetate) salt;

1,1-dimethylethyl[[4-[[[6-(aminoiminomethyl)-2-naphthalenyl]amino]-carbonyl]phenyl]methyl]carbamate,inoio(trifluoroacetate) salt;

N-[6-(aminoiminomethyl)-2-naphthalenyl)benzamide, mono(trifluoroacetate)salt;

1,1-dimethylethyl[[4-[[[6-(aminoiminonethyl)-2-naphthalenyl]amino]carbonyl]-cyclohexyll]methyl]carbamate,mono(trifluoroacetate) salt;

N-[6-(aminoiminomethyl)-2-naphthalenyl]-N′-(4-aminophenyl)urea,bis(trifluoroacetate) salt;

N-[6-(aminoiminomethyl)-2-naphthalenyl]-4-4-(aminomethyl)cyclohexanecarboxamide,bis(trifluoroacetate) salt;

N-[6-(aminoiminomethyl)-2-naphthalenyl]-N′-[(4-aminomethyl)phenyl]urea,bis(trifluoroacetate) salt;

6-(aminoiminomethyl)-N-(4-ethylphenyl)-2-naphthalenecarboxamide, acetatesalt;

6-(aminoiminomethyl)-N-(2-naphthalenyl)-2-naphthalenecarboxamide,mono(trifluoroacetate) salt;

6-(5-phenyl-2-oxazolyl)-2-naphthalenecarboximidamide,mono(trifluoroacetate) salt;

6-(5-phenyl-2-thiazolyl)-2-naphthalenecarboximidamide,mono(trifluoroacetate) salt;

6-(aminoiminomethyl)-N-(1,2,3,4-tetrahydro-6-quinolinyl)-2-naphthalenecarboxamide,bis(trifluoroacetate) salt;

6-[amino(hydroxyamino)methyl]-N-phenyl-2-naphthalenecarboxamide;

6-[4-[(hydroxymethyl)phenyl]methoxy]-2-naphthalenecarboximidamide,methanesulfonate salt;

6-(2-pyridinylethynyl)-2-naphthalenecarboximidamide,mono(trifluoroacetate) salt;

N-[4-(aminocarbonyl)phenyl]-6-(aminoiminomethyl)-2-naphthalenecarboxamide,mono(trifluoroacetate) salt;

6-(aminoiminomethyl)-N-(2-thiazolyl)-2-naphthalenecarboxamide,monohydrochloride

6-(aminoiminomethyl)-N-(6-methoxy-3-pyridinyl)-2-naphthalenecarboxamide,monohydrochloride

6-(aminoiminomethyl)-N-(1,3-benzodioxol-5-yl)-2-naphthalenecarboxamide,mono(trifluoroacetate) salt;

6-(aminoiminomethyl)-N-(1,2,3,4-tetrahydro-2,4-dioxo5-pyrimidinyl)-2-naphthalenecarboxamide,monohydrochloride

6-(aminoiminomethyl)-N-(3,5-difluorophenyl)-2-naphthalenecarboxamide,mono(trifluoroacetate) salt;

6-(aminoiminomethyl)-N-(1H-pyrazol-3-yl)-2-naphthalenecarboxamide,mono(trifluoroacetate) salt;

6-(aminoiminomethyl)-N-(5-methyl-3-isoxazolyll)-2-naphthalenecarboxamide,mono(trifuoroacetate) salt;

6-(aminoiminomethyl)-N-(pyrazinyl)-2-naphthalenecarboxamide,mono(trifluoroacetate) salt;

6-(aminoiminomethyl)-N-(6-methyl-2-pyridinyl)-2-naphthalenecarboxamide,mono(trifluoroacetate) salt;

6-(aminoiminomethyl)-N-(3,4,5-trimethoxyphenyl)-2-naphthalenecarboxamide,monohydrochloride

6-(aminoiminomethyl)-N-(3-methyl-2-pyridinyl)-2-naphthalenecarboxamide,bis(trifluoroacetate) salt;

6-(aminoiminomethyl)-N-(5-bromo-2-thiazolyll)-2-naphthalenecarboxamide,mono(trifluoroacetate) salt;

6-(aminoiminomethyl)-N-(5-methyl-2-pyridinyl)-2-naphthalenecarboxamide,mono(trifluoroacetate) salt;

6-(aminoiminomethyl)-N-(4-methyl-2-thiazolyl)-2-naphthalenecarboxamide,mono(trifluoroacetate) salt;

6-(aminoiminomethyl)-N-(6-quinolinyl)-2-naphthalenecarboxamide,bis(trifluoroacetate) salt;

6-(aminoiminomethyl)-N-(1H-indazol-6-yl)-2-naphthalenecarboxamide,bis(trifluoroacetate) salt;

6-(aminoiminomethyl)-N-(1H-indazol-5-yl)-2-naphthalenecarboxamide,bis(trifluoroacetate) salt;

6-(aminoiminomethyl)-N-(1H-indol-5-yl)-2-naphthalenecarboxamide,mono(trifluoroacetate) salt;

6-(aminoiminomethyl)-N-(5-pyrimidinyl)-2-naphthalenecarboxamide,mono(trifluoroacetate) salt;

6-(aminoiminomethyl)-N-(3-pyridazinyl)-2-naphthalenecarboxamide,mono(trifluoroacetate) salt;

6-(aminoiminomethyl)-N-(5-bromo-2-pyridinyl)-2-naphthalenecarboxamide,mono(trifluoroacetate) salt;

6-(aminoiminomethyl)-N-[3-(1-methylethoxy)phenyl]-2-naphthalenecarboxamide,mono(trifluoroacetate) salt;

6-(aminoiminomethyl)-N-(1H-imidazolyl)-2-naphthalenecarboxamide,bis(trifluoroacetate) salt;

6-[2-[4-(hydroxymethyl)phenyl]-1-cyclopropyl]-2-naphthalenecarboximidamide,mono(trifluoroacetate) salt;

N-(ethoxycarbonyl)-6-(2-phenyl-1-cyclopropyl)-2-naphthalenecarboximidamide

6-(aminoiminomethyl)-N-(2-methyl-6-quinolinyl)-2-naphthalenecarboxamide,bis(trifluoroacetate) salt;

6-(aminoiminomethyl)-N-(3-propoxyphenyl)-2-naphthalenecarboxamide,mono(trifluoroacetate) salt;

6-(aminoiminomethyl)-N-[3-(1-ethylpropoxy)phenyl]-2-naphthalenecarboxamide,mono(trifluoroacetate) salt;

6-(aminoiminomethyl)-N-[3-(cyclopentyloxy)phenyl]-2-naphthalenecarboxamide,mono(trifluoroacetate) salt;

6-(aminoiminomethyl)-N-(3-phenoxyphenyl)-2-naphthalenecarboxamide,mono(trifluoroacetate) salt;

6-(aminoiminomethyl)-N-[3-(phenylmethoxy)phenyl]-2-naphthalenecarboxamide,mono(trifluoroacetate) salt;

6-(aminoiminomethyl)-N-(3-ethoxyphenyl)-2-naphthalenecarboxamide,mono(trifluoroacetate) salt;

6-(aminoiminomethyl)-N-(4-nitrophenyl)-2-naphthalenecarboxamide,mono(trifluoroacetate) salt;

6-(aminoiminomethyl)-N-[3-(cyclobutylmethoxy)phenyl]-2-naphthalenecarboxamide,mono(trifluoroacetate)salt;

6-[amino(ethoxycarbonyl)imino]-N-[3-(1-methylethoxy)phenyl]-2-naphthalenecarboxamide;

6-(aminoiminomethyl)-4-[5-(ethylsulfonyl)-3-furanyl]-N-phenyl-2-naphthalenecarboxamide,monohydrochloride;

methyl [7-(aminoiminomethyl)-2-methoxy-1-naphthalenyl)carbamate,mono(trifluoroacetate) salt;

7-methoxy-8-(2-pyrimidinylamino)-2-naphthalenecarboximidamide,bis(trifluoroacetate) salt;

7-methoxy-8-[(phenylmethyl)aminol-2-naphthalenecarboximidamide,mono(trifluoroacetate) salt;

7-methoxy-8-(phenylamino)-2-naphthalenecarboximidamide,mono(trifluoroacetate) salt;

7-methoxy-8-[(4-methoxyphenyl)amino]-2-naphthalenecarboximidamide,mono(trifluoroacetate) salt;

(E)-3-[7-(aminoiminomethyl)-2-methoxy-1-naphthalenyl)-2-propenamide,mono(trifluoroacetate) salt;

7-methoxy-8-(3-oxo-1-cyclopenten-1-yl)-2-naphthalenecarboximidamide,mono(trifluoroacetate) salt;

methyl4-([[7-(aminoiminomethyl)-1-(2-pyrimidinylamino)-2-naphthalenyl]oxy]methyl]benzoate,mono(trifluoracetate) salt;

4-[[[7-(aminoiminomethyl)-1-(2-pyrimidinylamino)-2-naphthalenyl]oxy]methyl]benzoic acid, mono(trifluoroacetate) salt;

7-methoxy-8-(pyrazinyloxy)-2-naphthalenecarboximidamide,dimethanesulfonate salt;

7-methoxy-8-(phenylthio)-2-naphthalenecarboximidamide, methanesulfonate;

7-methoxy-8-(pyrazinylamino)-2-naphthalenecarboximidamide,bis(trifluoroacetate) salt;

methyl 5-[7-[(aminoiminomethyl)-2-napthalenyl]oxy]pentanoate,mono(trifluoroacetate) salt;

5-[[6-(aminoiminomethyl)-2-naphthalenyl]oxy]pentanoic acid,mono(trifluoroacetate) salt;

methyl4-[[[7-amino(hydroxyimino)methyl]-2-naphthalenyl]oxy]methyl]benzoate;

methyl 2-[[6-(aminoiminomethyl)-2-naphthhalenyl]oxy]acetate,mono(trifluoroacetate) salt;

7-[2-(4-morpholinyl)ethoxy]-2-naphthalenecarboximidamide,bis(trifluoroacetate) salt;

2-[[6-(aminoiminomethyl)-2-naphthalenyl]oxy]acetic acid,mono(trifluoroacetate) salt;

methyl 4-[6-(aminoiminomethyl)-2-naphthaleny]oxy]methyl]benzoate,mono(trifluoroacetate) salt;

methyl [7-(aminoiminomethyl)-1-naphthalenyl]methylcarbamate,mono(trifluoroacetate) salt;

propyl [7-(aminoiminomethyl)-1-naphthalenyl]carbamate,mono(trifluoroacetate) salt;

N-[7-(aminoiminomethyl)-1-naphthalenyl]-N′-methylurea,mono(trifluoroacetate) salt;

ethyl [7-(aminoiminomethyl)-1-naphthalenyl)carbamate,mono(trifluoroacetate) salt;

N-[7-(aminoiminomethyl)-1-naphthalenyl)propanamide,mono(trifluoroacetate) salt;

N-[7-(aminoiminomethyl)-1-naphthalenlyl)-2-methoxyacetamide,mono(trifluoroacetate) salt;

N-[7-(aminoiminomethyl)-1-naphthalenyl]urea, mono(trifluoroacetate)salt;

N-[7-(aminoiminomethyl)-1-naphthalenyl]-2-hydroxyacetamide,mono(trifluoroacetate) salt;

8-(2-pyrimidinylamino)-2-naphthalenecarboximidamide,bis(trifluoroacetate) salt;

8-amino-2-naphthalenecarboximidamide, bis(trifluoroacetate) salt;

8-(2-pyridinylamino)-2-naphthalenecarboximidamide, bis(trifluoroacetate)salt;

N-hydroxy-8-(2-pyrimidinylamino)-2-naphthalenecarboximidamide,mono(trifluoroacetate) salt;

6-(aminoiminomethyl)-4-(3-furanyl)-N-[4-(trifluoromethyl)phenyl]-2-naphthalenecarboxamide,mono(trifluoroacetate) salt;

6-(aminoiminomethyl)-4-(3-furanyl)-N-(4-pyridinyl)-2-naphthalenecarboxamide,dihydrochloride;

6-(aminoiminomethyl)-4-(3-furanyl)-N-(1H-pyrazol-3-yl)-2-naphthalenecarboxamide,dihydrochloride;

6-(aminoiminomethyl)-4-(3-furanyl)-N-(3-pyridinyl)-2-naphthalenecarboxamide,dihydrochloride;

methyl[7-(aminoiminomethyl)-3-[[[4-(aminomethyl)phenyl]amino]carbonyl]-1-naphathalenyl]carbamate,bis(trifluoroacetate) salt;

6-(aminoiminomethyl)-4-(3-furanyl)-N-(2-pyridinyl)-2-naphthalenecarboxamide,dihydrochloride;

6-(aminoiminomethyl)-4-(3-furanyl)-N-phenyl-2-naphthalenecarboxamide,monohydrochloride

6-(aminoiminomethyl)-4-[1-(methylsulfonyl)-1H-pyrazol-4-yl]-N-phenyl-2-naphthalenecarboxamide,monohydrochloride;

6-(aminoiminomethyl)-4-[5-(methylthio)-3-furanyl)]-N-phenyl-2-naphthalenecarboxamide,monohydrochloride;

6-(aminoiminomethyl)-N-[4-(aminomethyl)phenyl]-4-(2-pyrimidinylamino)-2-naphthalenecarboxamide,tris(trifluoroacetate) salt;

6-(aminoiminomethyl)-N-phenyl-4-(2-pyrimidinylamino)-2-naphthalenecarboxamide,mono(trifluoroacetate) salt;

N-[(4-(aminomethyl)phenyl]-6-[amino(hydroxyimino)methyl]-4-(2-pyrimidinylamino)-2-naphthalenecarboxamide,bis(trifluoroacetate) salt;

6-(aminoiminomethyl)-N-[4-(hydroxymethyl)phenyl]-4-(2-pyridinylamino)-2-naphthalenecarboxamide,mono(trifluoroacetate) salt;

methyl[3-[[[4-(aminomethyl)phenyl]amino]carbonyl]-7-[4-amino(hydroxyimino)methyl]-1-naphthalenyl]carbamate,bis(trifluoroacetate) salt;

6-(aminoiminomethyl)-N-phenyl-4-(tetrahydro-3-furanyl)-2-naphthalenecarboxamide,monohydrochloride;

6-[amino(hydroxyimino)methyl]-N-phenyl-4-(2-pyrimidinylamino)-2-naphthalenecarboxamide

6-(aminoiminomethyl)-4-[5-(ethylthio)-3-furanyl]-N-phenyl-2-naphthalenecarboxamide,monohydrochloride;

6-(aminoiminomethyl)-4-[5-(propylthio)-3-furanyl]-N-phenyl-2-naphthalenecarboxamide,monohydrochloride;

6-(aminoiminomethyl)-N-phenyl-4-(2-pyrrolidinyl)-2-naphthalenecarboxamide,mono(trifluoroacetate) salt;

6-(aminoiminomethyl)-4-[5-(propylsulfonyl)-3-furanyl]-N-phenyl-2-naphthalenecarboxamide,monohydrochloride;

6-(aminoiminomethyl)-4-[5-[methylthio)methyl]-3-furanyl]-N-phenyl-2-naphthalenecarboxamide,monohydrochloride;

6-(aminoiminomethyl)-4-[5-(methoxymethyl)-3-furanyl]-N-phenyl-2-naphthalenecarboxamide,monohydrochloride;

6-(aminoiminomethyl)-4-[5-(methylsulfonyl)-3-furanyl]-N-phenyl-2-naphthalenecarboxamide,mono(trifluoroacetate) salt; and

6-(aminoiminomethyl)-4-[5-(ethythio)tetrahydro-3-furanyl]-N-phenyl-2-naphthalenecarboxamide,monohydrochloride.

DETERMINATION OF UROKINASE INHIBITION

The efficacy of the compounds of this invention as urokinase inhibitorswas determined by measuring the inhibition of the urokinase enzymeAbbokinase (Abbott Laboratories, Abbott Park, Ill.) on substrate S-2444,of formula pyroGlu-Arg-pNA-HCl (DiaPharma Group, Inc. Distributor ofChromogenix) at 200 μM.

The assay was performed in a 96 well polystyrene, flat bottom plate in a50 mM Tris/0.15 M NaCl+0.5% Pluronic F-68 (Sigma P-5556), pH 7.4 (withHCl) buffer. The compounds of this invention, 10 mM in DMSO, werediluted with DMSO to eight half log concentrations, for example: 1200μM, 400 μM, 120 μM, 40 μM, 12 μM, 4 μM, 1 μM and 0.4 μM. Fourconcentrations were chosen, then 5 μl of each were diluted to a totalassay volume of 200 μl. The final compound concentrations in the assay,according to the above example, were 30 μM, 10μM, 3 μM, 1μM, 0.3 μM, 0.1μM, 0.03 μM and 0.01 μM, respectively. The substrate S-2444 was used at200 μM in the assay. Several vials were reconstituted as directed on thevial, aliquoted and stored frozen. The enzyme was further diluted inassay buffer and 10 μl was used in the assay. Enzyme concentration inthe assay was 2-3 nM. The assay was performed as follows: 175 μL ofbuffer was pipetted into the polystyrene plate, 5 μL solution of acompound of this invention in DMSO was added, the mixture was vortexed,10 μL of enzyme in buffer was added, the mixture was vortexed, 10μL ofsubstrate in water was added, the mixture was vortexed, and the platewas placed in a Spectromax® (Molecular Devices Corporation, Sunnyvale,Calif.) plate reader to follow the course of the reaction for 15 min at405 nm. The Spectromax® calculated the reaction rates which were used tocalculate percent inhibition of the compounds of this invention versusthe reaction rate of the enzyme in the absence of any inhibitor. TheKi's of the inhibitors were calculated from the percent inhibition andpreviously established Km. The compounds of this invention inhibiturokinase as shown by the data for representative examples in Table 1.

TABLE 1 Inhibitory Potency of Representative Compounds Against UrokinaseExample IC₅₀ (μM)  1 6.6  2 9.8  3 36  4 0.5  5 2.5  6 2.3  7 3.5  8 0.1 9 1.1  10 3.2  14 0.33  15 2.5  16 0.03  17 4.26  18 0.42  19 2.21  200.803  21 1.7  22 1.7  23 4.0  24 4.9  25 2.1  26 0.04  27 0.93  28 2.1 29 2.5  30 3.6  31 2.93  32 4.6  33 2.4  34 3.5  35 3.97  36 1.75  372.34  38 6.35  39 12.2  40 0.31  41 2.38  42 2.08  43 2.2  44 0.35  452.94  46 2.4  47 4.8  48 1.3  49 3.3  50 6.13  51 4.7  52 4.7  53 2.96 54 2.7  55 0.9  56 2.9  57 3.4  58 2.53  59 0.41  60 0.72  61 0.73  620.64  63 0.37  64 0.56  65 0.54  66 3.13  67 2.78  68 1.74  69 1.38  702.57  71 2.39  72 4.30  73 3.3  74 1.61  75 2.09  76 0.96  77 0.23  783.57  79 0.96  80 1.93  81 3.21  82 3.08  83 2.24  84 10.0  85 1.38  863.6  87 0.63  88 2.73  89 6.5  90 0.07  91 0.05  92 0.04  93 2.36  951.73  96 0.86  97 1.31  98 0.24  99 3.02 100 3.16 101 0.8 102 0.34 1030.57 104 1.2 105 0.84 106 0.76 107 2.34 108 0.996 109 2.85 110 111 4.17112 0.45 113 0.403 114 0.344 115 0.063 116 0.045 117 0.278 118 0.121 1194.41 120 0.93 121 0.89 122 0.33 123 1.24 124 0.12 125 0.23 126 0.87 1270.085 129 4.84 131 4.18 132 0.96 133 0.044 134 0.064 135 1.91 136 1.67137 0.82 138 0.46 139 2.64 140 0.46 141 0.00117 142 0.54 143 0.36 1441.26 145 2.59 146 0.372 147 0.213 148 0.81 149 3.8 150 0.16 152 0.083153 0.877 154 0.035 155 2.33 156 0.18 157 3.12 158 0.09 159 2.23 1602.62 161 1.59 162 1.33 163 0.03 164 0.45 165 0.00068 166 0.002 167 0.052168 0.003 170 0.695 171 >30 174 0.17 176 5.011 177 14.9 179 1.61 1800.097 181 8.92 182 >30 184 0.375 185 3.19 186 2.98 187 0.613 188 0.22189 1.3 190 0.565 191 0.887 192 1.6 193 0.85 194 0.56 195 1.3 196 0.62197 2.03 198 0.504 199 2.3 200 0.037 201 0.077 202 0.792 203 0.624 2040.331 205 0.337 206 5.73 207 4.12 208 0.96 209 0.82 210 0.78 211 0.072212 5.09 213 4.58 214 2.559 215 1.1 216 >30 217 0.67 218 0.086 219 0.103220 0.03 221 0.52 222 0.346 223 0.07 224 1.773 225 0.104 226 >30 2270.015 228 0.025 229 0.117 230 0.103 231 0.015 232 0.123

Pharmaceutical Compositions

The present invention also provides pharmaceutical compositions whichcomprise compounds of the present invention formulated together with oneor more non-toxic pharmaceutically acceptable cankers. Thepharmaceutical compositions may be specially formulated for oraladministration in solid or liquid form, for parenteral injection or forrectal administration.

The pharmaceutical compositions of this invention can be administered tohumans and other animals orally, rectally, parilleieally , inntacisteinally, intravaginally, intraperitoneally or topically (such aspowders, ointments or drops), bucally or as an oral or nasal spray. Theterm “parenteral” administration, as used herein, refers to modes ofadministration which include intravenous, intramuscular,intraperitoneal, intrasternal, subcutaneous and intraarticular injectionand infusion.

Pharmaceutical compositions of this invention for parenteral injectioncomprise pharmaceutically acceptable sterile aqueous or nonaqueoussolutions, dispersions, suspensions or emulsions as well as sterilepowders for reconstitution into sterile injectable solutions ordispersions just prior to use. Examples of suitable aqueous andnonaqueous carriers, diluents, solvents or vehicles include water,ethanol, polyols (such as glycerol, propylene glycol, polyethyleneglycol and the like), and suitable mixtures thereof, vegetable oils(such as olive oil) and injectable organic esters such as ethyl oleate.Proper fluidity can be maintained, for example, by the use of coatingmaterials such as lecithin, by the maintenance of the required particlesize in the case of dispersions and by the use of surfactants.

These compositions may also contain adjuvants such as preservative,wetting agents, emulsifying agents and dispersing agents. Prevention ofthe action of microorganisms may be ensured by the inclusion of variousantibacterial and anitifungal agents, for example, paraben,chlorobutanol, phenol sorbic acid and the like. It may also be desirableto include isotonic agents such as sugars, sodium chloride and the like.Prolonged absorption of the injectable pharmaceutical form may bebrought about by the inclusion of agents (such as aluminum monostearateand gelatin) which delay absorption.

In some cases, in order to prolong the effect of the drug, it isdesirable to slow the absorption of the drug from subcutaneous orintramuscular injection. This may be accomplished by the use of a liquidsuspension of crystalline or amorphous material with poor watersolubility. The rate of absorption of the drug then depends upon itsrate of dissolution which, in turn, may depend upon crystal size andcrystalline form. Alternatively, delayed absorption of a parenterallyadministered drug form is accomplished by dissolving or suspending thedrug in an oil vehicle.

Injectable depot forms are made by forming microencapsule matrices ofthe drug in biodegradable polymers such as polylactide-polyglycolide.Depending upon the ratio of drug to polymer and the nature of theparticular polymer employed, the rate of drug release can be controlled.Examples of other biodegradable polymers include poly(orthoesters) andpoly(anhydrides). Depot injectable formulations are also prepared byentrapping the drug in liposomes or microemulsions which are compatiblewith body tissues.

The injectable formulations can be sterilized, for example, byfiltration through a bacterial-retaining filter or by incorporatingsterilizing agents in the form of sterile solid compositions which canbe dissolved or dispersed in sterile water or other sterile injectablemedia just prior to use.

Solid dosage forms for oral administration include capsules, tablets,pills, powders and granules. In such solid dosage forms, the activecompound is mixed with at least one inert, pharmaceutically acceptableexcipient or carrier such as sodium citrate or dicalcium phosphateand/or a) fillers or extenders such as starches, lactose, sucrose,glucose, mannitol and silicic acid; b) binders such ascarboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone,sucrose and acacia; c) humectants such as glycerol; d) disintegratingagents such as agar—agar, calcium carbonate, potato or tapioca starch,alginic acid, certain silicates and sodium carbonate; e) solutionretarding agents such as paraffin; f) absorption accelerators such asquaternary ammonium compounds; g) wetting agents such as cetyl alcoholand glycerol monostearate; h) absorbents such as kaolin and bentoniteclay and i) lublicants such as talc, calcium stearate, magnesiumstearate, solid polyethylene glycols, sodium lauryl sulfate and mixturesthereof. In the case of capsules, tablets and pills, the dosage form mayalso comprise buffering agents. Solid compositions of a similar type mayalso be employed as fillers in soft and hard-filled gelatin capsulesusing such excipients as lactose or milk sugar as well as high molecularweight polyethylene glycols and the like.

The solid dosage forms of tablets, dragees, capsules, pills, andgranules can be prepared with coatings and shells such as entericcoatings and other coatings well known in the pharmaceutical formulatingart. They may optionally contain opacifying agents and may also be of acomposition such that they release the active ingredient(s) only, orpreferentially, in a certain part of the intestinal tract, optionally orin delayed fashion. Examples of embedding compositions which can be usedinclude polymeric substances and waxes.

The active compounds may also be in micro-encapsulated form, ifappropriate, with one or more of the above-mentioned excipients.

Liquid dosage forms for oral administration include pharmaceuticallyacceptable emulsions, solutions, suspensions, syrups and elixirs. Inaddition to the active compounds, the liquid dosage forms may containinert diluents commonly used in the art such as water or other solvents,solubilizing agents and emulsifiers such as ethyl alcohol, isopropylalcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzylbenzoate, propylene glycol, 1,3-butylene glycol, dimethyl formamide,oils (in particular, cottonseed, groundnut, corn, germ, olive, castor,and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethyleneglycols and fatty acid esters of sorbitan and mixtures thereof.

Besides inert diluents, the oral compositions may also include adjuvantssuch as wetting agents, emulsifying and suspending agents, sweetening,flavoring and perfuming agents. Suspensions, in addition to the activecompounds, may contain suspending agents such as ethoxylated isostearylalcohols, polyoxyethelene sorbitol and sorbitan esters, microcrystallinecellulose, aluminum metahydroxide, bentonite, agar—agar, and tragacanthand mixtures thereof. Compositions for rectal or vaginal administrationare preferably suppositories which can be prepared by mixing thecompounds of this invention with suitable non-intitating excipients orcarriers such as cocoa butter, polyethylene glycol or a suppository waxwhich are solid at room temperature but liquid at body temperature andtherefore melt in the rectum or vaginal cavity and release the activecompound.

Compounds of the present invention can also he administered in the formof liposomes. As is known in the art, liposomes are generally derivedfrom phospholipids or other lipid substances. Liposomes are formed bymono- or multi-lamellar hydrated liquid crystals which are dispersed inan aqueous medium. Any non-toxic, physiologically acceptable andmetabolizable lipid capable of forming liposomes can be used. Thepresent compositions in liposome form can contain, in addition to acompound of the present invention, stabilizers, preservatives,excipients and the like. The preferred lipids are the phospholipids andthe phosphatidyl cholines (lecithins), both natural and synthetic.Methods to form liposomes are known in the art, for example, Prescott,Ed., Methods in Cell Biology, Volume XIV, Academic Press, New York, N.Y.(1976), p. 33 et seq.

Dosage forms for topical administration of a compound of this inventioninclude powders, sprays, ointments and inhalants. The active compound ismixed under sterile conditions with a pharmaceutically acceptablecarTier and any needed preservatives, buffers or propellants which maybe required. Opthalmic formulations, eye ointments, powders andsolutions are also contemplated as being within the scope of thisinvention.

Actual dosage levels of active ingredients in the pharmaceuticalcompositions of this invention may be varied so as to obtain an amountof the active compound(s) that is effective to achieve the desiredtherapeutic response for a particular patient, compositions, and mode ofadministration. The selected dosage level will depend upon the activityof the particular compound, the route of administration, the severity ofthe condition being treated and the condition and prior medical historyof the patient being treated. However, it is within the skill of the artto start doses of the compound at levels lower than required for toachieve the desired therapeutic effect and to gradually increase thedosage until the desired effect is achieved. Generally dosage levels ofabout 1 to about 50, more preferably of about 5 to about 20 mg, ofactive compound per kilogram of body weight per day when administeredorally to a mammalian patient. If desired, the etfective daily dose maybe divided into multiple doses for purposes of administration, e.g. twoto four separate doses per day.

PREPARATION OF COMPOUNDS OF THIS INVENTION

The compounds of this invention may be prepared by a variety ofsynthetic routes. Representative procedures are outlined in thefollowing Schemes 1-6.

Abbreviations

Abbreviations which have been used in the descriptions of the schemesand the examples that follow are: THF for tetrahydrofuran; DMF forN,N-dimethylformamide; OEt₂ for diethyl ether; EDC for1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride; NMM forN-methylmorpholine; LDA for lithium diisopropylamide; TFA fortrifluoroacetic acid; DMSO for dimethylsulfoxide; DMAP for4-(N,N-dimethylamino)pyridine; HATU for O-(azabenzotriazole-1-yl)-N, N,N′, N′-tetramethyluroniumhexafluorophosphate; Boc fortert-butylcarbonyloxy; DDQ for2,3-dichiloro-5,6-dicyano-1,4-benzoquinone; Bn for benzyl; DPPA fordiphenylphospholryl azide; DCC for dicyclohexylcarbodiimide; EDC for1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride; SEM for2-(trimethylsilyl)ethoxymethyl; dppf for1,1′-bis(diphenylphosphino)ferrocene; and dba for dibenzylideneacetone.Starting materials, reagents and solvents were purchased from AldrichChemical Company (Milwaukee, Wis.).

As shown in Scheme 1, naphthalenecarbonitriles 4, 5 and 6 were preparedby treating 3-cyanopropionaldehyde diethyl acetal 2 with a strong basesuch as lithium diisopropylamide then treating the resulting anion withthe appropriately substituted benzaldehyde 1 followed by cyclization andaromatization of the corresponding cyanohydrins 3 with a Lewis acid suchas sulfuric acid.

A, B and C are hydrogen and —L_(A)R_(A), —L_(B)R_(B), —L_(C)R_(C)

—L_(A)—, —L_(B)— and —L_(C)— are —O—

R_(A), R_(B) and R_(C) are alkyl

4: A is hydrogen; B and C are OCH₃

5: A,B and C are OCH₃

6: A and B are OCH₃, and C is hydrogen

As shown in Scheme 2, selective demethylation of 4 with a Lewis acidsuch as AlCl₃ or BBr₃, preferably AlCl₃, provided 7. 7 was treated witha base such as potassium carbonate, sodium hydride or cesium fluoridefollowed by R_(C)—X, wherein X is a leaving group, to provide 8 (—L_(C)—is —O—). Alternatively, treatment of 7 with trifluoromethanesulfonicanhydride or1,1,1-trifluoro-N-phenyl-N-[(tinfluoromethyl)sulfonyl]methanesulfonamideprovided 9, which may be treated with R_(C)—B(OH)₂,

wherein R_(C) is unsubstituted or substituted aryl or heterocycle, inthe presence of a palladium catalyst, preferably Pd(II)Cl₂(dba) orPd(Ph₃P)₄, and base, preferably cesium fluoride or potassium carbonate,to provide 10. Alternatively, 9 may be treated with R_(C)—NR₁R₂, whereinR_(C) is unsubstituted or substituted aryl or heterocycle, and at leastone of R₁ or R₂ is hydrogen, in the presence of a strong base, such aspotassium t-butoxide, and a catalyst, such as Pd(II)Cl₂(dba), to provide11.

As shown in Scheme 3, selective O-triflation of 12 followed byprotection of the amino group of the resulting 13 with acid-labilecarbobenzlyoxy provided 14. Conversion of 14 to 15 was achieved with KCNin the presence of a palladium catalyst, preferablytris(dibenzylideneacetone)dipalladium(0)-chloroform adduct, anddeprotection of 15 to provide 16 was accomplished with acid, preferably30% HBr in acetic acid. Treatment of 15 with acylating agentsR_(C)C(O)Cl and base, preferably triethylamine, diisopropylethylamine orpotassium carbonate provided intermediate 17.

As shown in Scheme 4, selective demethylation of the 8-methoxy group of18 with a Lewis acid such as AlCl₃ or BBr₃, preferably AlCl₃, wasfollowed by reprotection of phenol 19 by alkylation with Bn—X, wherein Xis Cl, Br or I, in the presence of a base such as potassium carbonate,sodium hydride or cesium fluoride. 20 was prepared by deprotonation ofthis intermediate with a strong, non-nucleophilic base such as lithium,sodium or potassium diisopropylamide or alkoxide followed by treatmentwith an alkyl formate, preferably ethyl formate to provide enol 20.Treatment of 20 with hydroxylamine provided isoxazole 21 which may beopened with lithium, sodium or potassium alkoxide, preferably sodiummethoxide, to provide 22. Carbonyl reduction with concomitant alkeneformation with achieved with sodium borohydride to provide 23; andaromatization with DDQ and catalytic debenzylation with hydrogen and apalladium catalyst, preferably palladium on carbon, provided 24. 24 wasalkylated by treatment with a base such as potassium carbonate, sodiumhydride or cesium fluoride followed by treatment R_(C)—X.

As shown in Scheme 5, monohydrolysis of 25 with one equivalent of basesuch as lithium, sodium or potassium hydroxide provided the acid-ester26. Treatment of 26 with thionyl chloride or oxalyl chloride/DMFfollowed by treatment with ammonia provided amide 27. Treatment of 27with a dehydrating agent such as thionyl chloride or phosphorusoxychloride provided nitrile 28.

Regioselective nitration of 28 with nitric acid/potassium nitratefollowed by reduction of the nitro group with a palladium catalyst,preferably palladium on carbon, provided intermediate 31, which wastreated with R_(C)C(O)Cl or R_(C)OC(O)Cl and base, preferablydiisopropylethylamine or potassium carbonate, to provide 37.

Hydrolysis of 28 with one equivalent of lithium, sodium or potassiumhydroxide to form carboxylic acid 29 followed by treatment with DPPA orthionyl chloride then sodium azide and hydrolysis of the intermediateisocyanate 32 with acid, preferably sulfuric acid, provided amine 33.Altematively, treatment of 32 with a primary or secondary amine providedurea 34 (—L_(A)—=—NR₁C(X)R₂—, wherein X is O).

29 may be coupled to primary or secondary amines, and 33 may be coupledto carboxylic acids to form amides 35 and 36, respectively. In eithercase, the amines and carboxylic acids are coupled using a dehydratingagent such as DCC, EDC or HATU.

As shown in Scheme 6, intermediates wherein —L_(A)— is —C—≡C— or —C═C—were prepared by treatment of of 38 with a triflating agent, preferablytrifluoromethanesulfonyl anhydride, to form 39, followed by coupling ofthe appropriate substituted alkenes or unsubstituted or substitutedalkynes using a palladium catalyst, preferably palladium (II) acetate,to form 40.

As shown in Scheme 7, conversion of the nitrite intermediates to thecarboximidamide urokinase inhibitors 41 was achieved by three methods:(1) treatment of the intermediate carbonitriles with a non-nucleophilicbase such as lithium, sodium or potassium bis(trimethylsilylamide),preferably lithium bis(trimethylsilylamide) followed by hydrolysis withacid, preferably HCl; (2) treatment of the nitrile with acid, preferablyHCl, followed by treatment with ammonium acetate; and (3) treatment ofthe nitrile with H₂S followed by treatment with ammonia gas in methanol.Of the three methods, the H₂S/NH₃/methanol method is preferred. Thecompounds of the invention were precipitated as hydrochloride or methanesulfonate salts or were purified by reversed phase medium pressurechromatography to form mono- or bis-trifluoroacetate salts.

SYNTHETIC METHODS

The foregoing may be better understood by reference to the followingexamples which illustrate the methods by which the compounds of theinvention may be prepared and are not intended to limit the scope of theinvention as defined in the appended claims.

EXAMPLE 1 7,8-Dimethoxy-2-naphthalenecarboximidamidemono(trifluoroacetate) salt EXAMPLE 1A7,8-Dimethoxy-2-naphthalenecarbonitrile

A solution of freshly prepared LDA in THF at −78° C. was treateddropwise with 3-cyanopropionaldehyde diethyl acetal (3.0 g) in THF (5mL), stirred for 1 h, treated with 2,3-dimethoxybenzaldehyde (3.2 g) inTHF (5 mL), warmed to room temperature over 90 min, treated with water(40 mL), concentrated and extracted with chloroform. The organic layerwas washed with brine, dried (MgSO₄) and concentrated to provide 1.5 gof a yellow oil.

MS (DCI/NH₃) m/e 341 (M+H₂O)⁺.

A solution of the oil in methanol (5 mL) was added dropwise to 20%aqueous sulfuric acid (100 mL) at 90° C. The solution was heated for 90min, cooled to room temperature and extracted with chloroform. Thecombined organic extracts are washed with brine, dried (MgSO₄) andconcentrated to provide 1.0 g of a brown solid which was purified byflash chromatography on silica gel with 3:1 hexane/ethyl acetate toprovide 800 mg of the title compound.

MS (DCI/NH₃) m/e 231 (M+H₂O)⁺.

EXAMPLE 1B 7,8-Dimethoxy-2-naphthalenecarboximidamidemono(trifluoroacetate) salt

A solution of Example 1 (200 mg) in THF (5 mL) at 0° C. was treated withlithium bis(trimethylsilylamide) (1.0 M in hiexane, 1.1 mL), stirred for18 h at room temperature, treated with 10% HCl (10 mL), stirred for 24 hat room temperature, concentrated and purified by medium pressure liquidchromatography on a 30 cm×2 cm C-18 column (40 micron, J. T Baker) withUV detection at 250 nM with solvent mixtures in a gradient ranging from90%A (0.1% aq TFA)/10%B (methanol) to 10%A/90%B over 160 min at a flowrate of 5 mL/min (fractions were collected every 2 min for 100 min andanalyzed by TLC (10:1:1 acetonitrile/water/acetic acid) for product) toprovide 100 mg of the title compound.

¹H NMR (300 MHz, DMSO-d₆) δ 4.41 (s, 3H), 4.62 (s, 3H), 7.41 (d, 1H),7.43 (dd, 1H), 7.60 (d, 1H), 7.80 (d, 1H), 8.49 (d, 1H), 9.31 (bs, 2H),9.48 (bs, 2H);

MS (DCI/NH₃) m/e 231 (M+H)⁺. Anal. calcd for C₁₃H₁₄N₂O₂.TFA: C, 52.33;H, 4.39; N, 8.14. Found: C, 51.91; H, 4.35; N, 8.05.

EXAMPLE 2 6,7,8-trimethoxy-2-naphthalenecarboximidamidemono(trifluoroacetate) salt EXAMPLE 2A6,7,8-trimethoxy-2-naphthalenecarbonitrile

The title compound was prepared as described in Example 1A butsubstituting 2,3,4-trimethoxybenzaldehyde for2,3-trimethoxybenzaldehyde.

MS (DCI/NH₃) m/e 261 (M+H₂O)⁺.

EXAMPLE 2B 6,7,8-trimethoxy-2-naphthalenecarboximidamidemono(trifluoroacetate) salt

The title compound was prepared and purified as described in Example 1Bto provide 100 mg of the title compound.

¹H NMR (DMSO-d₆, 300 MHz) δ 3.91 (s, 3H), 3.98 (s, 3H), 4.06 (s, 3H),7.36 (s, 1H), 7.75 (dd, 1H) 7.99 (d, 1H), 8.49 (d, 1H), 9.18 (bs, 2H),9.38 (bs, 2H); MS (DCI/NH₃) m/e 261 (M+H)⁺. Anal. calcd forC₁₄H₁₆N₂O₃.TFA: C, 51.34; H, 4.58; N, 7.48. Found: C, 50.91; H, 4.25; N,7.35.

EXAMPLE 3 6,7-dimethoxy-2-naphthalenecarboximidamidemono(trifluoroacetate) salt EXAMPLE 3A6,7-dimethoxy-2-naphthalenecarbonitrile

The title compound was prepared as described in Example 1A butsubstituting 3,4-dimethoxybenzaldehyde for 2,3-dimethoxy-benzaldehyde toprovide 1.3 g of the title compound.

MS (DCI/NH₃) m/e 231 (M+H₂O)⁺.

EXAMPLE 3B 6,7-dimethoxy-2-naphthalenecarboximidamidemono(trifluoroacetate) salt

The title compound was prepared and purified as described in Example 1Bto provide 100 mg of the title compound.

¹H NMR (DMSO-d₆, 300 MHz) δ 3.92 (s, 3H), 3.94 (s, 3H), 7.41 (s, 1H),7.44 (s, 1H), 7.69 (dd, 1H), 7.93 (d, 1H), 8.49 (d, 1H), 9.18 (bs, 2H),9.38 (bs, 2H); MS (DCI/NH₃) m/e 231 (M+H)⁺. Anal. calcd forC₁₃H₁₄N₂O₂.TFA: C, 52.33; H, 4.39; N 8.14. Found: C, 52.15; H, 4.20; N8.10.

EXAMPLE 4 2-[(7-Aminoiminomethyl-2-methoxy-1-naphthalenyl)oxy]acetamidemono(trifluoroacetate) salt EXAMPLE 4A7-Methoxy-8-hydroxynaphthalene-2-carbonitrile

A solution of Example 1A (1 g) in methylene chloride (100 mL) at 0° C.was treated with AlCl₃, stirred for 4 h at 0° C. and at room temperaturefor 18 h, poured into water (200 mL) containing 6N HCl (20 mL), stirredfor 1 h and diluted with methylene chloride (100 mL). The layers wereseparated, and the organic layer was washed with brine and dried (MgSO₄)to provide 810 mg of the title compound as an off-white solid.

MS (DCI/NH₃) m/e 217 (M+H₂O)⁺.

EXAMPLE 4B 1,1-Dimethylethyl2-[(7-Cyano-2-methoxy-1-naphthalenyl)oxy]acetate

A slurry Example 4A (100 mg), K₂CO₃ (70 mg), t-butyl bromoacetate (120mg) and tetrabutylammonium iodide (25 mg) in DMF (3 mL) was stirred for18 h at room temperature, diluted with water (20 mL) and extracted withethyl acetate. The organic extract was washed with saturated NaHCO₃ andbrine, dried (Na₂SO₄) and concentrated to provide 200 mg of the titlecompound as a clear oil.

MS (DCI/NH₃) m/e 331 (M+H₂O)⁺.

EXAMPLE 4C 2-[(7-Aminoiminomethyl-2-methoxy-1-naphthalenyl)oxy]acetamidemono(trifluoroacetate) salt

Example 4B (100 mg) in methanol (5 mL) at 0° C. was treated with HCl(g),stirred for 18 h at room temperature and concentrated to provide anoff-white solid. The solid was treated with 2N NH₃ in methanol (10(mL),heated at 50° C. for 3.5 h, cooled and concentrated to a yellow solidwhich was purified as described in Example 1B to provide 10 mg of thetitle compound.

¹H NMR (300 MHz, DMSO-d₆) δ 3.93 (s, 3H), 4.79 (s, 2H), 7.55 (d, 2H),7.65 (dd, 1H), 7.72 (d, 1H), 7.85 (d, 1H), 8.09 (d, 1H), 8.7 (d, 1H),9.03 (bs, 2H), 9.45 (bs, 2H); MS (DCI/NH₃) m/e 274 (M+H)⁺. Anal. calcdfor C₁₄H₁₅N₃O₃.TFA: C, 49.62; H, 4.16; N, 10.85. Found: C, 49.33; H,4.03; N, 10.50.

EXAMPLE 5 7-Benzyloxy-8-iodo-2-naphthalenecarboximidamidemono(trifluoroacetate) salt EXAMPLE 5A7-Benzyloxy-8-iodo-2-naphthalenecarbonitrile

The title compound was prepared as described in Example 43A butsubstituting benzyl bromide for propyl iodide.

MS (DCI/NH₃) m/e 403 (M+NH₄)⁺.

EXAMPLE 5B 7-Benzyloxy-8-iodo-2-naphthalenecarboximidamidemono(trifluoroacetate) salt

The title compound was prepared from Example 5A according to theprocedure of Example 1B.

¹H NMR (300 MHz, DMSO-d₆) δ 9.30 (br, 4H), 8.44 (s, 1H), 8.12 (d, 1H),7.71 (d, 2H), 7.67 (dd, 1H), 7.57 (d, 2H), 7.45-7.34 (m, 3H), 5.45 (s,2H); MS (DCI/NH₃) m/e 403 (M+H)⁺. Anal. calcd for C₁₈H₁₅N₂OI.TFA: C,46.53; H, 3.12; N, 5.43. Found: C; 46.55; H, 3.10; N, 5.19.

EXAMPLE 6 Methyl[(7-aminoiminomethyl-2-methoxy-1-naphthalenyl)oxy]acetatemono(trifluoroacetate) salt EXAMPLE 6A Methyl[(7-cyano-2-methoxy-1-naphthalenyl)oxy]acetate

A solution of Example 4A (600 mg), Cs₂CO₃ (500 mg), t-butyl bromoacetate(120 mg) and tetrabutylammonium iodide (25 mg) in DMF (15 mL) wasstirred for 18 h at room temperature, diluted with water (20 mL) andextracted with ethyl acetate. The organic extract was washed withsaturated NaHCO₃ and brine, dried (Na₂SO₄) and concentrated to provide800 mg of the title compound as a clear oil.

MS (DCI/NH₃) m/e 331 (M+H₂O)⁺.

EXAMPLE 6B Methyl[(7-aminoiminomethyl-2-methoxy-1-naphthalenyl)oxy]acetatemono(trifluoroacetate) salt

Example 6A (100 mg) in methanol (30 mL) at 0° C. was treated withHCl(g), stirred for 18 h at room temperature and concentrated to providean off-white solid. The solid was treated with ammonium acetate (100 mg)in methanol (10 mL), heated at 40° C. for 15 h, cooled and concentratedto a yellow solid which was purified as described in Example 1B toprovide 10 mg of the title compound.

¹H NMR (300 MHz, DMSO-d₆) δ 3.65 (s, 3H), 3.93 (s, 3H), 4.79 (s, 2H),7.65 (dd, 1H), 7.72 (d, 1H), 7.85 (d, 1H), 8.09 (d, 1H), 8.7 (d, 1H),9.03 (bs, 2H), 9.45 (bs, 2H); MS (DCI/NH₃) m/e 289 (M+H)⁺. Anal. calcdfor C₁₅H₁₆N₂O₄.TFA: C, 50.75; H, 4.26; N, 6.96. Found: C, 50.42; H,4.03; N, 6.77.

EXAMPLE 7 [(7-aminoiminomethyl-2-methoxy-1-naphthalenyl)oxy]acetic acidmono(trifluoroacetate) salt

A solution of Example 6B (100 mg) and LiOH.H₂O (150 mg) in 1:1 THF/H₂O(10 mL) at 5° C. was stirred 45 min and concentrated to provide anoff-white solid. The solid was dissolved in 1N HCl (20 mL), stirred 48 hat room temperature and filtered. The resulting white solid was purifiedas described in Example 1B to provide 20 mg of the title compound.

¹H NMR (300 MHz, DMSO-d₆) δ 3.93 (s, 3H), 4.79 (s, 2H), 7.65 (dd, 1H),7.72 (d, 1H), 7.85 (d, 1H), 8.09 (d, 1H), 8.7 (d, 1H), 9.23 (bs, 2H),9.45 (bs, 2H); MS (DCI/NH₃) m/e 275 (M+H)⁺. Anal. calcd forC₁₄H₁₄N₂O₄.TFA: C, 49.49; H, 3.89; N, 7.21. Found: C, 47.53; H, 3.71; N,6.83.

EXAMPLE 8N-[4-(Aminomethyl)phenyl]-6-aminoiminomethyl-2-naphthalenecarboxamidebis(trifluoroacetate) saltN-[4-(Aminomethyl)phenyl]-6-aminoiminomethyl-2-naphthalenecarboxamidebis(trifluoroacetate) salt EXAMPLE 8A 2,6-Naphthalenedicarboxylic acid,monomethyl ester

A suspension of dimethyl 2,6-naphthalenedicarboxylic acid (39.6 g, 162mmole) in dioxane (1.20 L) was heated at 70-80° C. until all soliddissolved, slowly treated with 1 equivalent of KOH in methanol, stilledfor additional 30 minutes at 70° C., cooled to room temperature,filtered and washed with dioxane and diethyl ether, dissolved in water,treated with 1N HCl until the aqueous layer was acidic to pH paper,filtered, washed with water and dried under vacuum to provide 33 g of awhite powder.

MS (DCI/NH₃) m/e 231 (M+H)⁺.

EXAMPLE 8B 6-(Chlorocarbonyl)-2-naphthalenecarboxylic acid, methyl ester

A suspension of Example 8A (15 g, 65 mmole) in toluene (190 mL) wastreated with thionyl chloride (20 mL, 276 mmole) then DMAP (15 mg),heated at reflux for 1 h and heated at 85° C. for an additional 35 min.The condenser was replaced with a distilling head and 60 mL of solventwas removed. The thick precipitate which formed while cooling to roomtemperature was triturated with hexane and filtered to provide 4.8 g ofwhite solid.

MS (DCI/NH₃) m/e 249 (M+H)⁺.

EXAMPLE 8C 6-(Aminocarbonyl)-2-naphthalenecarboxylic acid, methyl ester

A solution of Example 8B (15 g, 60.3 mmole) in methylene chloride (400mL) at room temperature was treated with dry ammonia gas to precipitatethe product. The mixture was stirred for an additional 15 min andfiltered. The solid was washed with water and dried under vacuum toyield 13.3 g of a white powder.

MS (DCI/NH₃) m/e 230 (M+H)⁺.

EXAMPLE 8D 6-Cyano-2-naphthalenecarboxylic acid, methyl ester

A suspension of Example 8C (31 g, 135 mmole) in trimethyl phosphate (450mL) was treated with triphosgenie (27 g, 136 mmole), stirred for 20 minat room temperature and heated in an oil bath at 80° C. for 1 h. Theproduct precipated from the solution while cooling to room temperature.The thick slutty was treated with water and filtered, and the whitesolid was thoroughly washed with water and dried under vacuum to provide26.3 g of the title compound.

MS (DCI/NH₃) m/e 212 (M+H)⁺.

EXAMPLE 8E 6-Cyano-2-naphthalenecarboxylic acid

Example 8D (1.9 g, 9 mmole) in 1:1 THF/H₂O (40 mL) was treated withLiOH.H₂O (1.9 g, 45 mmole), stilled 90 min at room temperature andconcentrated to a thick slurry. The slurry was dissolved in water (20mL), acidified to pH 2 with solid citric acid and extracted with ethylacetate. The combined organic extracts were washed with brine, dried(Na₂SO₄) and concentrated to provide 1.6 g of the title compound as awhite solid.

MS (DCI/NH₃) m/e 197 (M+H)⁺.

EXAMPLE 8F tert-Butoxycarbonylamino-4-aminomethylaniline

4-Aminomethylaniline (2 g) in 2:1 THF/H₂O (30 mL) was treated with Bocanhydride (3.93 g), stinred at room temperature for 18 h, diluted withwater and concentrated to white slurry. The slurry was dissolved inethyl acetate, washed with water and brine, dried (Na₂SO₄) andconcentrated to provide 2.4 g of a yellow solid.

MS (DCI/NH₃) m/e 223 (M+H)⁺.

EXAMPLE 8G N-[4-(aminomethyl)phenyl]-6-cyano-2-naphthalenecarboxamide

A solution of Example 8E (200 mg) and hunig's base (180 μL) in DMF (5mL) at 5° C. was treated with HATU (193 mg), stirred for 1 h at 5° C.,treated with Example 8F (120 mg) and diisopropylethylamine (100 μL) inDMF (5 mL), stirred for 8 h at room temperature, diluted with ethylacetate (100 mL), washed sequentially with 1N H₃PO₄, saturated sodiumbicarbonate and brine, dried (Na₂SO₄) and concentrated to provide ayellow oil which was purified on silica gel with 1% methanol/methylenechloride to provide 200 mg of the title compound.

MS (DCI/NH₃) m/e 419 (M+H₂O)⁺.

EXAMPLE 8HN-[4-(aminomethyl)phenyl]-6-aminoiminomethyl-2-naphthalenecarboxamidebis(trifluoroacetate) salt

The title compound was prepared from Example 8G (200 mg) by theprocedure and purification from Example 5B to provide 37 mg of the titlecompound.

¹H NMR (300 MHz, DMSO-d₆) δ 4.08 (m, 2H), 7.45 (d, 2H), 7.88 (d, 2H),7.95 (dd, 1H), 8.18 (dd, 1H), 8.20 (bs, 3H), 8.23 (d, 1H), 8.35 (d, 1H),8.58 (s, 1H), 8.70 (s, 1H), 9.39 (s, 2H), 9.55 (s, 2H), 10.68 (s, 1H);MS (DCI/NH₃) m/e 319 (M+H)⁺. Anal. calcd for C₁₉H₁₇N₄O.TFA: C, 50.56; H,3.69; N, 10.25; Found: C, 50.18; H, 3.59; N, 10.11.

EXAMPLE 9N-[4-(amino)phenyl]-6-aminoininonethyl-2-naphthalenecarboxamidebis(trifluoroacetate) salt EXAMPLE 9AN-[4-(amino)phenyl]-6-cyano-2-naphthalenecarboxamide

The title compound was prepared according to the procedure described forExample 8G but substituting 1,4-diaminobenzene for Example 8F. MS(DCI/NH₃) m/e 288 (M+H)⁺.

EXAMPLE 9BN-[4-(amino)phenyl]-6-aminoiminomethyl-2-naphthalenecarboxamidebis(trifluoroacetate) salt

The title compound was prepared with Example 9A (100 mg) following theprocedure and purification from Example 6B.

¹H NMR (300 MHz, DMSO-d₆) δ 7.15 (d, 2H), 7.75 (d, 2H), 7.95 (dd, 1H),8.18 (dd, 1H), 8.23 (d, 1H), 8.35 (d, 1H), 8.58 (s, 1H), 8.70 (s, 1H),9.25 (s, 2H), 9.48 (s, 2H), 10.58 (s, 1H); MS (DCI/NH₃) m/e 305 (M+H)⁺.Anal. calcd for C₁₈H₁₆N₄O.2TFA: C, 49.63; H, 3.41; N, 10.52; Found: C,46.57; H, 3.62; N, 10.66.

EXAMPLE 101-[(7-Aminoiminomethyl-2-methoxy-1-naphthalenyl)oxy]-3-hydroxypropanemono(trifluoroacetate) salt EXAMPLE 10A1-[(7-Cyano-2-methoxy-1-naphthalenyl)oxy]-3-[(2-tetrahydro-2H-pyranyl]oxy)propanemono(trifluoroacetate) salt

A suspension of Example 4A (200 mg) and Cs₂CO₃ (0.32 g) in DMF (15 mL)was treated with 2-(3-bromopropyl)-tetrahydro-2H-pyran (0.25 g), stirredat room temperature for 18 h then diluted with water (100 mL) and ethylacetate (50 mL). The organic layer was separated, washed with 10)%citric acid, water and brine, dried (MgSO₄) and concentrated to provide320 mg of an oil.

MS (DCI/NH₃) m/e 323 (M+H)⁺.

EXAMPLE 10B1-[(7-Aminoiminomethyl-2-methoxy-1-naphthalenyl)oxy]-3-hydroxypropanemono(trifluoroacetate) salt

Example 10A (0.3 g) was processed and purified according to theprocedure of Example 1B to provide 110 mg of an off-white solid.

¹H NMR (300 MHz, DMSO-d₆) δ 1.97 (q, 2H), 3.67 (t, 2H), 4.20 (t, 2H),7.61-7.70 (m, 3H), 7.84 (d,1H), 8.08 (d, 1H), 8.50 (d, 1H); MS (DCI/NH₃)m/e 275 (M+H)⁺. Anal. calcd for C₁₃H₁₃N₃O₂.TFA.0.75H₂O: C, 50.81; H,5.14; N, 6.97. Found: C, 51.23; H, 5.28; N, 6.97.

EXAMPLE 11 8-amino-2-naphthalenecarbonitrile hydrobromide EXAMPLE 11A2-Trifluoromethanesulfonyloxy-8-aminonaphthalene

A solution of 8-amino-2-naphthol (10 g) and triethylamine (12 mL) indioxane (200 mL) was treated with N-phenyltrifluoromethane sulfonimide(25 g) in dioxane (80 mL), stirred for 4 h and concentrated. Theresulting dark brown solid was triturated with hexane and filtered toprovide 12 g of the title compound as a brown solid.

MS (DCI/NH₃) m/e 292 (M+H)⁺.

EXAMPLE 11B2-Trifluoromethanesulfonyloxy-8-carbonylbenzlyoxyaminonaphthalene

A solution of Example 11A (2 g) in 10% aq Na₂CO₃ (20 mL) and dioxane(250 mL) was treated with benzylchloroformate (2 mL) in dioxane (20 mL),stirred at room temperature for 5 h then extracted with ethyl acetate.The organic layer was dried (MgSO₄) and concentrated, and the crudeproduct was chromatographed on silica gel with 7:1 hexane/ethyl acetateto provide 2.5 g (86%) of the title compound.

MS (DCI/NH₃) m/e 443 (M+NH₄)⁺.

EXAMPLE 11C 8-(N-carbonylbenzyloxy)-2-naphthalenecarbonitrile

Tris(dibenzylideneacetone)dipalladium(0)-chlorofolm adduct (120 mg),1,1′-bis(diphenylphosphino)-ferrocene (260 mg), potassium cyanide (766mg), Example 11B (2.5 g) and N-methyl-2-pyrrolidione (5 mL) werecombined sequentially, stirred at room temperature until a yellowreaction complex formed then warmed to 80° C. for 40 min. The dark brownreaction mixture was cooled to room temperature and chromatographed onsilica gel with 9:1 hexane/ethyl acetate to provide 1.5 g of the titlecompound as a colorless solid.

MS (DCI/NH₃) m/e 292 (M+NH₄)⁺.

EXAMPLE 11D 8-Amino-2-naphthalenecarbonitrile hydrobromide

Example 11C (1.4 g) was treated with a solution of 30% HBr in aceticacid (5 mL) and stirred at room temperature for 6 h. The reactionmixture was treated with diethyl ether and filtered to provide 1.1 g ofthe title compound as a yellow solid.

MS (DCI/NH₃) m/e 186 (M+NH₄)⁺.

EXAMPLE 12 General Acylation Procedure

A suspension of Example 10D (1 equivalent), triethylamine (1 equivalent)and DMAP (0.25 equivalents) in methylene chloride (0.3M) was treateddropwise with the appropriate acid chloride (1.1 equivalents) inmethylene chloride (0.3 M), stirred at room temperature for 30 min andtreated with water (5 mL). The organic layer was dried (MgSO₄),concentrated and used in following reactions without furtherpurification.

EXAMPLE 13 General Amidine Synthesis Procedure

A solution of crude acylation products from Example 12 (ca. 100 mg) atroom temperature in 10:1 pyridine:triethylamine (10 mL) was treated withhydrogen sulfide for 5 min, stirred at room temperature for 18 h,diluted with water (50 mL) and extracted with ethyl acetate. The ethylacetate was dried (MgSO₄) and concentrated. The residue was dissolved inacetone (30 mL), treated with methyl iodide (2 mL), refluxed for 1 hour,evaporated to dryness, redissolved in methanol (25 mL), treated withammonium acetate (100 mg), stirred for 18 h at room temperature,concentrated and purified as described in Example 1B to provide Examples14-20 as white solids.

EXAMPLE 14 8-(carbonylbenzyloxy)amino-2-naphthalenecaboximidamidemono(trifluoroacetate) salt

¹H NMR (DMSO-d₆, 300 MHz) δ 5.14 (s, 2H), 7.36-7.50 (m, 5H), 7.67-7.90(m, 4H), 8.14 (d, 1H), 8.67 (s, 1H), 9.08 (s, 2H), 9.37 (s, 2H), 9.78(s, 1H); MS (DCI/NH₃) m/e 320 (M+H)⁺. Anal. calcd forC₁₉H₁₅N₃O₂.1.5TFA.0.5H₂O: C, 52.91; H, 3.94; N, 8.41. Found: C, 52.86;H, 4.07; N, 8.18.

EXAMPLE 15 N-[7-(aminoiminomethyl)-1-naphthalenyl)acetamidemono(trifluoroacetate) salt

¹H NMR (DMSO-d₆, 300 MHz) δ 4.19 (s, 3H), 7.66-7.88 (m, 3H), 8.12-8.16(m, 2H), 8.69 (s, 1H), 8.98 (d, 1H), 9.16 (s, 2H), 9.47 (s, 2H), 10.14(s, 1H); MS (DCI/NH₃) m/e 228 (M+H)⁺. Anal. calcd forC₁₄H₁₂N₃O.1.2TFA.0.25H₂O: C, 50.18; H, 4.02; N, 11.40. Found: C, 50.62;H, 4.47; N, 10.90.

EXAMPLE 16 Methyl [7-(aminoiminomethyl)-1-naphthalenyl)carbamatemono(trifluoroacetate) salt

¹H NMR (DMSO-d₆, 300 MHz) δ 3.88 (s, 3H), 7.67-7.85 (m, 4H), 8.14 (d,1H), 8.6 (s, 1H), 8.28 (s, 3H), 9.67 (s, 1H); MS (DCI/NH₃) m/e 244(M+H)⁺. Anal. calcd for C₁₃H₁₃N₃O₂.TFA: C, 50.43; H, 3.95; N, 11.76.Found: C, 50.12; H, 4.05; N, 11.61.

EXAMPLE 17 Methyl3-[[7-(aminoiminomethyl)-1-naphthelenyl]amino]-3-oxopropionatemono(trifluoroacetate) salt

¹H NMR (DMSO-d₆, 300 MHz) δ 3.69 (s, 2H), 3.71 (s, 3H), 7.69 (m, 4H),8.18 (d, 1H), 8.58 (s, 1H), 9.11 (s, 2H), 9.48 (s, 2H); MS (DCI/NH₃) m/e286 (M+H)⁺. Anal. calcd for C₁₅H₁₄N₃O₃.1.1TFA.H₂O: C, 48.18; H, 4.26; N,9.80. Found: C, 48.30; H, 4.09; N, 9.58.

EXAMPLE 18N-[7-(aminoiminomethyl)-1-naphthalenyl]-2-(phenylmethoxy)acetamidemono(trifluoroacetate) salt

¹H NMR (DMSO-d₆, 300 MHz) δ 4.29 (s, 2H), 4.73 (s, 2H), 7.33-7.48 (m,5H), 7.69 (m, 4H), 8.17 (d, 1H), 8.47 (s, 1H), 9.21 (br, 4H), 10.0 (s,1H); MS (DCI/NH₃) m/e 334 (M+H)⁺. Anal. calcd for C₂₀H₁₈N₃O₂.1TFA.H₂O:C, 56.77; H, 4.76; N, 9.03. Found: C, 56.84; H, 4.49; N, 8.93.

EXAMPLE 19N-[7-(aminoiminomethyl)-1-naphthelenyl]-1,3-benzodioxole-5-carboxamidemono(trifluoroacetate) salt

¹H NMR (DMSO-d₆, 300 MHz) δ 6.19 (1H, 2H), 7.12 (d, 1H), 7.65-7.79 (m,5H), 7.97 (d, 1H), 8.20 (s, 1H), 8.53 (s, 1H), 9.2 (br s, 3H), 10.35 (s,2H); MS (DCI/NH₃) m/e 334 (M+H)⁺. Anal. calcd for C₁₈H₁₄N₃O₂.TFA: C,55.82; H, 3.68; N, 9.30. Found: C, 55.69; H, 33.61; N, 9.23.

EXAMPLE 20N-[7-(aminoiminomethyl)-1-naphthalenyl]benzenemethanesulfonamidemono(trifluoroacetate) salt

¹H NMR (DMSO-d₆, 300 MHz) δ 4.60 (s, 2H), 7.32-7.33 (m, 5H), 7.67-7.70(m, 2H), 7.82 (d, 1H), 7.92 (d, 1H), 8.17 (s, 1H), 8.7() (s, 1H), 9.14(s, 2H), 9.35 (s, 2H), 9.19 (s, 1H); MS (DCI/NH₃) m/e 340 (M+H)⁺. Anal.calcd for C₁₈H₁₇N₃O₂S.TFA.H₂O: C, 50.95; H, 4.28; N, 8.91; Found: C,50.76; H, 3.70; N, 8.65.

EXAMPLE 211-[(7-aminoiminomethyl-2-methoxy-1-naphthalenyl)oxy]-3-bromopropanemono(hydrochloride) salt EXAMPLE 21A1[(7-Cyano-2-methoxy-1-naphthalenyl)oxy]-3-bromopropanemono(hydrochloride) salt

The title compound was prepared from Example 4A, 1,3-dibromopropane andthe procedure of Example 10A.

MS (DCI/NH₃) m/e 337 (M+NH₄)⁺.

EXAMPLE 21B1-[(7-Aminoiminomethyl-2-methoxy-1-naphthalenyl)oxy]-3-bromopropanemono(hydrochloride) salt

The title compound was prepared from Example 21A and the procedure ofExample 1B. After HCl hydrolysis, the solution was cooled to 0° C., andthe white solid which precipitated was filtered and dried to provide thetitle compound.

¹H NMR (300 MHz, DMSO-d₆) δ 2.35 (m, 2H), 3.86 (t, 2H), 4.00 (s, 3H),4.25 (t, 2H), 7.65 (dd, 1H), 7.70 (d, 1H), 7.90 (d, 1H), 8.10 (d, 1H),8.55 (s, 1H), 9.15 (br s, 2H), 9.42 (br s, 2H); MS (DCI/NH₃) m/e 337(M+H)⁺. Anal. calcd for C₁₅H₁₇BrN₂O₂.HCl.0.75H₂O: C, 46.53; H, 5.08; N,7.23. Found: C, 46.65; H, 5.11; N, 7.16.

EXAMPLE 22 3-[(7-Aminoiminomethyl-2-methoxy-1-naphthalenyl)oxy]propenemono(trifluoroacetate) salt EXAMPLE 22A3[(7-Cyano-2-methoxy-1-naphthalenyl)oxy]propene

The title compound was obtained as a biproduct from the procedure ofExample 21A. MS (DCI/NH₃) m/e 257 (M+NH₄)⁺.

EXAMPLE 22B 3-[(7-Aminoiminomethyl-2-methoxy-1-naphthalenyl)oxy]propenemono(trifluoroacetate) salt

The title compound was prepared from Example 22A and the procedure andpurification in Example 1B.

¹H NMR (300 MHz, DMSO-d₆) δ 4.00 (s, 3H), 4.70 (d, 2H), 5.22 (d, 1H),5.42 (d, 1H), 6.18 (m, 1H), 7.62 (dd, 1H), 7.85 (d, 1H), 8.10 (d, 1H),8.50 (s, 1H), 9.12 (br s, 2H), 9.45 (br s, 2H); MS (DCI/NH₃) m/e 257(M+H)⁺. Anal. calcd for C₁₅H₁₆N₂O₂.TFA.0.25H₂O: C, 54.47; H, 4.71; N,7.47. Found: C, 54.61; H, 4.38; N, 7.40.

EXAMPLE 231-[(7-Aminoiminomethyl-2-methoxy-1-naphthalenyl)oxy]-3-phenylpropanemono(hydrochloride) salt EXAMPLE 23A1-[(7-Cyano-2-methoxy-1-naphthalenyl)oxy]-3-phenylpropane

The title compound was prepared form Example 4A,1-bromo-3-phenylpropane, and the procedure of Example 10A. MS (DCI/NH₃)m/e 335 (M+NH₄)⁺.

EXAMPLE 23B1-[(7-Aminoiminomethyl-2-methoxy-1-naphthalenyl)oxy]-3-phenylpropanemono(hydrochloride) salt

The title compound was prepared from Example 23A and the procedure ofExample 21B.

¹H NMR (300 MHz, CD₃OD) δ 2.21 (m, 2H), 2.94 (t, 2H), 4.00 (s, 3H), 4.22(t, 2H), 7.18 (m, 1H), 7.28 (m, 4H), 7.62 (m, 2H), 7.79 (d, 1H), 8.02(d, 1H), 8.62 (s, 1H); MS (DCI/NH₃) m/e 335 (M+H)⁺. HRMS (FAB) calcd m/efor C₂₁H₂₃N₂O₂.HCl: 335.1760 (M+H)⁺. Found m/e 335.1762.

EXAMPLE 241-[(7-Aminoiminomethyl-2-methoxy-1-naphthalenyl)oxy]-3-[1-(3,4-dimethoxy)phenyl]propanemono(hydrochloride) salt EXAMPLE 24A1-Bromo-3-(3,4-dimethoxyphenyl)propane

The title compound was prepared from 3-(3,4-dimethoxyphenyl)-1-propanolas described in Journal of the American Chemical Society, 95, 8749(1973), which is incorporated herein by reference, to provide the titlecompound.

MS (DCI/NH₃) m/e 276 (M+NH₄)⁺.

EXAMPLE 24B1-[(7-Cyano-2-methoxy-1-naphthalenyl)oxy]-3-[1-(3,4-dimethoxy)phenyl]propane

The title compound was prepared from Examples 4A and 24A and theprocedure of Example 10A.

MS (DCI/NH₃) m/e 395 (M+NH₄)⁺.

EXAMPLE 24C1-[(7-Aminoiminomethyl-2-methoxy-1-naphthalenyl)oxy]-3-[1-(3,4-dimethoxy)phenyl]propanemono(hydrochloride) salt

The title compound was prepared from Example 24B and the procedure ofExample 21B.

¹H NMR (300 MHz, DMSO-d₆) δ 2.11 (m, 2H), 2.80 (t, 2H), 3.74 (s, 6H),3.98 (s, 3H), 4.15 (t, 2H), 6.75-6.92 (m, 3H), 7.65 (dd, 1H), 7.70 (d,1H), 7.86 (d, 1H), 8.10 (d, 1H), 8.55 (s, 1H), 9.15 (br s, 2H), 9.53 (brs, 2H); MS (DCI/NH₃) m/e 395 (M+H)⁺. Anal. calcd forC₂₃H₂₆N₂O₄.HCl.0.5H₂O: C, 62.79; H, 6.42; N, 6.37. Found: C, 63.08; H,6.38; N, 6.17.

EXAMPLE 25 7-Methoxy-8-(2-furanyl)-2-naphthalenecarboximidamidemono(trifluoroacetate) salt EXAMPLE 25A7-Methoxy-8-trifluoromethanesulfonyloxy-2-naphthalenecarbonitrile

A solution of Example 4A (310 mg) in methylene chloride (5 mL) at 0° C.was treated with1,1,1-trifluoro-N-phenyl-N-[(trifluoromethyl)sulfonyl]methanesulfonamide(614 mg) and triethylamine (240 mL), stirred for 18 h at roomtemperature, diluted with methylene chloride (100 mL), washed with waterand 20% aq NaOH, dried (MgSO₄) and concentrated to provide 560 mg of thetitle compound as a white solid.

MS (DCI) m/e 349 (M+H₂O)⁺.

EXAMPLE 25B Furan-2-boronic acid

A solution of furan (5.3 mL, 73 mmole) in diethyl ether (67 mL) at −20°C. was treated with n-butyllithium (2.5 M in hexanes, 26 mL, 65 mmole),stirred for 2 hours at −20° C. and transferred by cannula to a −20° C.solution of triisopropyl borate (33 mL, 147 mmole) in diethyl ether (17mL). The thick mixture was warmed to room temperature, treated with 3NHCl (200 mL) and extracted with diethyl ether. The extracts were washedwith 1N KOH, and the KOH layer was cooled to 0° C. and acidified with 6NHCl. The acidic solution was extracted with diethyl ether, and theacidic ether extracts were washed with brine, dried (MgSO₄) andconcentrated to provide the title compound.

¹H NMR (300 MHz, DMSO-d₆) δ 6.45 (dd, 1H), 7.05 (t, 1H), 7.80 (dd, 1H),8.19 (s, 2H).

EXAMPLE 25C 7-Methoxy-8-(2-furanyl)-2-naphthalenecarbonitrile

Example 25A (1.10 mmol) was combined with Pd(OAc)₂ (0.11 mmol) and1,1′-bis(diphenylphosphino)ferrocene (0.22 mmol) in DMF (5 mL), stirredfor 10 min, treated with Example 25B (1.32 mmol) and Cs₂CO₃ (3.3 mmol),heated at 85° C. for 6 h, cooled to room temperature and chromatographedon silica gel with 10% ethyl acetate/hexane to provide the titlecompound.

MS (DCI/NH₃) m/e 250 (M+H)⁺.

EXAMPLE 25D 8-(2-Furanyl)-7-methoxy-2-naphthalenecarboximidamidemono(trifluoroacetate) salt

The title compound was prepared from Example 25C and the procedure andpurification in Example 1B.

¹H NMR (300 MHz, DMSO-d₆) δ 3.97 (s, 3H), 6.73 (m, 1H), 6.80 (m, 1H),7.64 (dd, 1H), 7.78 (d, 1H), 7.91 (m, 1H), 8.16 (d, 1H), 8.20 (d, 1H),8.30 (s, 1H), 9.08 (br s, 2H), 9.40 (br s, 2H); MS (DCI/NH₃) m/e 267(M+H)⁺. Anal. calcd for C₁₆H₁₄N₂O₂.TFA: C, 56.85; H, 3.98; N, 7.37.Found: C, 56.68; H, 3.67; N, 7.35.

EXAMPLE 26 Methyl6-(aminoiminomethyl)-4-[(methoxycarbonyl)amino]-2-naphthalenecarboxylatemono(trifluoroacetate) salt EXAMPLE 26A2-Cyano-1-nitro-6-carboxynaphthalene methyl ester

A solution of 2-cyano-6-methylnaphthoate (5.2 g) in concentrated sufuricacid (75 mL) at 0° C. was treated with potassium nitrate (1.03 eq) inone portion, stirred for 10 min, poured onto ice (500 g) and extractedwith ethyl acetate. The ethyl acetate layer was washed with water, 1NNaOH and brine, dried (MgSO₄), treated with silica gel and filtered.Concentration of the ethyl acetate to ca. 200 mL precipitated theproduct. The mixture was heated until all solid dissolved, treated withMeOH (20 mL) and ether (20 mL) and stirred overnight. The resultingsolid was filtered and washed with methanol to provide 2.31 g of thetitle compound as a cream-colored solid. The mother liqueuor wasevaporated, treated with methylene chloride (250 mL) then solid silicagel, filtered and concentrated. Crystalization from ethylacetate/methanol provided an additional 1.6 g of product for a totalyield: 3.91 g (62%).

MS (DCI/NH₃) m/e 257 (M+H)⁺.

EXAMPLE 26B 2-Cyano-1-amino-6-carboxynaphthalene methyl ester

A solution of Example 26A (1 g, 3.9 mmole) and 10% Pd on carbon (112 mg)in ethyl acetate (80 mL) was stirred under 1 atm of hydrogen for 9 h,purged with nitrogen for 1 h, filtered and evaporated to provide 810 mg(92%) of the title compound as a yellow solid.

MS (DCI/NH₃) m/e 227 (M+NH₄)⁺.

EXAMPLE 26C 6-Cyano-4-[(melthoxycarbonyl)amino]-2-naphthalenecarboxylicacid, methyl ester

A solution of Example 26B (2.50 mmol) in methylene chloride (40 mL) wastreated sequentially with diisopropylethylamine (2 mL) andmethylchloroformate (195 μL, 2.52 mmole), stirred for 2 h, treated withmethanol (10 mL), stirred for an additional 10 minutes, diluted withmethylene chloride (60 mL), washed with water and brine, dried (MgSO₄)and evaporated. The residue was purified on silica gel using 10% ethylacetate/hexane to provide 280 mg (59%) of light yellow solid.

MS (DCI/NH₃) m/e 285 (M+H)⁺.

EXAMPLE 26D Methyl6-(aminoiminomethyl)-4-[(methoxycarbonyl)amino]-2-naphthalenecarboxylatemono(trifluoroacetate) salt

The title compound was prepared using Example 26C (125 mg, 0.44 mmol)and the procedure in Example 40D to provide 35 mg of a white solid.

¹H NMR (DMSO-d₆) δ 3.78 (s, 3H), 3.95 (s, 3H), 7.89 (dd, 1H), 8.37-8.40(m, 3H), 8.53 (s, 1H), 8.740 (s, 1H) 9.18 (br s, 2H), 9.45 (br s, 2H),9.90 (s, 1H), 8.42 (s, 1H) 8.63 (d, 1H), 9.18 (br s, 4H), 10.58 (s, 1H);MS (DCI/NH₃) m/e 302 (M+H)⁺. Anal. calcd for C₁₅H₁₅N₃O₄.TFA.1.5H₂O: C,46.16; H, 4.33; N, 9.50. Found: C, 45.96; 46.16; H, 4.06; N, 9.12.

EXAMPLE 27 (E)-{7-Methoxy-8-[2-(Phenyl)ethenyl]}-2-naphthaleneimidamidemono(trifluoroacetate) salt EXAMPLE 27A(E)-{7-Methoxy-8-[2-(Phenyl)ethenyl]}-2-naphthalenecarbonitrile

Example 25A and styrene boronic ester, prepared according to theprocedure of Journal of the American Chemical Society, 97 5249 (1975),which is incorporated herein by reference, was processed according tothe procedure described in Example 26B to provide the title compound.

MS (DCI/NH₃) m/e 303 (M+NH₄)⁺.

EXAMPLE 27B (E)-{7-Methoxy-8-[2-(Phenyl)ethenyl]}-2-naphthaleneimidamidemono(trifluoroacetate) salt

The title compound was prepared from Example 27A and the procedure ofExample 1B.

¹H NMR (300 MHz, DMSO-d₆) δ 3.98 (s, 3H), 7.28 (t, 2H), 7.39 (t, 2H),7.64 (m, 5H), 8.00 (d, 1H), 8.10 (d, 1H), 8.62 (s, 1H), 9.22 (br s, 2H),9.42 (br s, 2H); MS (DCI/NH₃) m/e 303 (M+H)⁺. Anal. calcd forC₂₀H₁₈N₂O.TFA: C, 63.46; H, 4.60; N, 6.73. Found: C, 63.10; H, 4.73; N,6.43.

EXAMPLE 28 6-(4-Phenylbutynyl)-2-naphthalenecarboximidamidemono(trifluoroacetate) salt EXAMPLE 28A6-Hydroxy-2-naphthalenecarbonitrile

A solution of 6-bromo-2-naphthol (25.0 g, 112 mmol) and copper(I)cyanide (11 g, 123 mmol) in DMF (30 mL) was heated at 135° C. for 18 h,cooled, diluted with ethyl acetate (50 mL), triturated with 10% aqsodium hydroxide and filtered through Celite®. The filtrate wasacidified to pH 2 and extracted with ethyl acetate. The combinedextracts were concentrated, dissolved in ethanol (150 mL) and trituratedwith water to precipitate 14.01 g of the title compound.

MS (DCI/NH₃) m/e 170 (M+H)⁺.

EXAMPLE 28B 6-(Trifluoromethanesulfonyloxy)-2-naphthalenecarbonitrile

A solution of Example 28A (14.01 g, 82.8 mmol) and triethylamine (9.2 g,91.1 mmol) in methylene chloride (40 mL) at 0° C. was treated dropwisewith trifluoromethylsulfonic anhydride (28 g, 99.4 mmol), warmed to 25°C. for 48 h, concentrated, redissolved in ethanol (50 mL) and trituratedwith water to precipitate 8.4 g of the title compound.

MS (DCI/NH₃) m/e 319 (M+NH₄)⁺.

EXAMPLE 28C 6-(4-Phenylbutynyl)-2-naphthalenecarbonitrile

The title compound was prepared from Example 28B, 4-phenyl-1-butyne andthe procedure of Example 57B.

MS (DCI/NH₃) m/e 299 (M+NH₄)⁺.

EXAMPLE 28D 6-(4-Phenylbutynyl)-2-naphthalenecarboximidamidemono(trifluoroacetate) salt

The title compound was prepared from Example 28C and the procedure ofExample 1B.

¹H NMR (300 MHz, DMSO-d₆) δ 2.80 (t, 2H), 2.95 (t, 2H), 7.22 (m, 1H),7.36 (m, 4H), 7.58 (d, 1H), 7.82 (d, 1H), 8.05 (d, 1H), 8.10 (d, 2H),8.45 (s, 1H), 9.10 (br s, 2H), 9.42 (br s, 2H); MS (DCI/NH₃) m/e 299(M+H)⁺. Anal. calcd for C₂₁H₁₈N₂.TFA.0.75H₂O: C, 64.86; H, 4.85; N,6.58. Found: C, 64.78; H, 4.64; N, 6.03.

EXAMPLE 29 7-(2-Hydroxyethoxy)-8-iodo-2-naphthalenecarboximidamidemono(trifluoroacetate) salt EXAMPLE 29A3-[[(1,1-Dimethylethyl)dimethylsilyl]oxy]-1-propanol,4-nitrobenzenesulfonate

A solution of 3-t-butlydimethylsiloxy-1-propanol, prepared by the methodof McDougal, et al. JOC, 1986, 51, 3388, which is incorporated herein byreference, (7.6 g, 40 mmol) and diisopropylethylamine (10.4 mL, 60 mmol)in methylene chloride (200 mL) at 0° C. was treated withp-nitrophenylsulfonyl chloride (9.7 g, 44 mmol), stirred for 3 h, pouredinto saturated NaHCO₃ and extracted with diethyl ether. The extractswere washed with brine, dried (Na₂SO₄), and concentrated. The residuewas chromatographed on silica gel with 5% ethyl acetate/hexanes toprovide 6.00 g of the title compound.

MS (DCI/NH₃) m/e 395 (M+NH₄)⁺.

EXAMPLE 29B7-[2-[[(1,1-Dimethylethyl)dimethylsilyl]oxy]ethoxy]-8-iodo-2-naphthalenecarbonitrile

The title compound was prepared in a manner analogous to that of Example43A but substituting Example 29A for propyl iodide.

MS (DCI/NH₃) m/e 468 (M+H)⁺.

EXAMPLE 29C

7-(2-Hydroxyethoxy)-8-iodo-2-naphthalenecarbonitrile

The title compound was prepared in a manner analogous to that of Example53F but substituting Example 29B for Example 53E.

MS (DCI/NH₃) m/e 357 (M+H)⁺.

EXAMPLE 29D 7-(2-Hydroxyethoxy)-8-iodo-2-naphthalenecarboximidamidemono(trifluoroacetate) salt

The title compound was prepared from Example 29B according to theprocedure of Example 1B.

¹H NMR (300 MHz, DMSO-d₆) δ 1.96 (m, 2H), 3.69 (t, 2H), 4.33 (t, 2H),4.58 (br, 1H), 7.63 (d, 1H), 7.66 (dd, 1H), 8.12 (dd, 2H), 8.42 (s, 1H),9.20 (s, 2H), 9.53 (s, 2H); MS (DCI/NH₃) m/e 245 (M+H)⁺; Anal. calcd forC₁₃H₁₂N₂O₂I.TFA.0.21H₂O: C, 53.07; H, 4.85; N, 7.74. Found: C, 53.07; H,4.75; N, 7.65.

EXAMPLE 30 7-(2-Hydroxyethoxy)-2-naphthalenecarboximidamidemono(trifluoroacetate) salt EXAMPLE 30A7-(2-Hydroxyethoxy)-2-naphthalenecarbonitrile

Example 29B (120 mg, 0.26 mmol), palladium(II)Cl₂dppf (46 mg, 0.03 mmol)and diisopropylamine (263 mg, 2.6 mmol) were heated in a sealed tube for2 h at 100° C., cooled to room temperature, diluted with ethyl acetate,washed with water, dried (Na₂SO₄), and concentrated. The residue waspurified on silica gel with 15% ethyl acetate/hexanes to provide 85 mgof the title compound.

MS (DCI/NH₃) m/e 342 (M+H)⁺.

EXAMPLE 30B 7-(2-Hydroxyethoxy)-2-naphthalenecarboximidamidemono(trifluoroacetate) salt

The title compound was prepared from Example 29B according to theprocedure of Example 1B.

¹H NMR (300 MHz, DMSO-d₆) δ 1.96 (m, 2H), 3.69 (t, 2H), 4.33 (t, 2H),4.58 (br, 1H), 7.63 (d, 1H), 7.66 (dd, 1H), 8.12 (dd, 2H), 8.42 (s, 1H),9.20 (s, 2H), 9.53 (s, 2H); MS (DCI/NH₃) m/e 228 (M+H)⁺; Anal. calcd forC₁₄H₁₅N₂O₂.TFA: C, 53.78; H, 4.51; N, 7.84. Found: C, 53.60; H, 4.30; N,7.81.

EXAMPLE 31 6-(4-Methyl-1-pentynyl)-2-naphthalenecarboximidamidemono(trifluoroacetate) salt EXAMPLE 31A6-(4-Methyl-1-pentynyl)-2-naphthalenecarbonitrile

The title compound was obtained from Example 28B, 4-methyl-1-pentyne andthe procedure of Example 57B.

MS (DCI/NH₃) m/e 251 (M+NH₄)⁺.

EXAMPLE 31B 6-(4-Methyl-1-pentynyl)-2-naphthalenecarboximidamidemono(trifluoroacetate) salt

The title compound was prepared from Example 31A and the procedure ofExample 1B.

¹H NMR (300 MHz, DMSO-d₆) δ 1.05 (d, 6H), 1.90 (m, 1H), 2.20 (d, 2H),7.62 (dd, 1H), 7.82 (dd, 1H), 8.09 (d, 1H), 8.12 (d, 1H), 8.18 (s, 1H),8.48 (s, 1H), 9.12 (br s, 2H), 9.42 (br s, 2H); MS (DCI/NH₃) m/e 251(M+H)⁺. Anal. calcd for C₁₇H₁₈N₂.TFA: C, 62.63; H, 5.26; N, 7.69. Found:C, 64.85; H, 5.32; N, 7.46.

EXAMPLE 32 6-(5-Phenylpentynyl)-2-naphthalenlecarboximidamidemono(trifluoroacetate) salt EXAMPLE 32A6-(5-Phenylpentynyl)-2-naphthalenecarbonitrile

The title compound was obtained from Example 28B, 5-phenyl-1-pentyne andthe procedure of Example 57B.

MS (DCI/NH₃) m/e 313 (M+NH₄)⁺.

EXAMPLE 32B 6-(5-Phenylpentynyl)-2-naphthalenecarboximidamidemono(trifluoroacetate) salt

The title compound was prepared from Example 32A and the procedure ofExample 1B.

¹H NMR (300 MHz, DMSO-d₆) δ 1.90 (m, 2H), 2.80 (t, 2H), 3.39 (t, 2H),7.19-7.37 (m, 5H), 7.62 (dd, 1H), 7.82 (dd, 1H), 8.08 (d, 1H), 8.15 (d,1H), 8.18 (s, 1H), 8.48 (s, 1H), 9.15-9.45 (br d, 4H);

MS (DCI/NH₃) m/e 313 (M+H)⁺. Anal. calcd for C₂₂H₂₀N₂.TFA: C, 67.60; H,4.96; N, 6.57. Found: C, 67.32; H, 5.21; N, 6.27.

EXAMPLE 33 6-(3-Phenyl-1-propynyl)-2-naphthalenecarboximidamidemono(trifluoroacetate) salt EXAMPLE 33A6-(3-Phenyl-1-propynyl)-2-naphthalenecarbonitrile

The title compound was obtained from Example 28B, 3-phenyl-1-propyne andthe procedure of Example 57B.

MS (DCI/NH₃) m/e 285 (M+NH₄)⁺.

EXAMPLE 33B 6-(3-Phenyl-1-propynyl)-2-naphthalenecarboximidamidemono(trifluoroacetate) salt

The title compound was prepared from Example 33A and the procedure ofExample 5B.

¹H NMR (300 MHz, DMSO-d₆) δ 4.00 (s, 2H), 7.28-7.50 (m, 5H), 7.70 (dd,1H), 7.85 (dd, 1H), 8.09 (d, 1H), 8.15 (d, 1H), 8.21 (s, 1H), 8.49 (s,1H), 9.21 (br s, 2H), 9.45 (br s, 2H); MS (DCI/NH₃) m/e 285 (M+H)⁺.Anal. calcd for C₂₀H₁₆N₂.TFA.0.25H₂O: C, 65.59; H, 4.38; N, 6.95. Found:C, 65.43; H, 3.95; N, 6.70.

EXAMPLE 34 6-(Phenylethynyl)-2-naphthalenecarboximidamidemono(trifluoroacetate) salt EXAMPLE 34A6-(Phenylethynyl)-2-naphthalenecarbonitrile

The title compound was obtained from Example 28B, phenylacetylene andthe procedure of Example 57B. MS (DCI/NH₃) m/e 271 (M+NH₄)⁺.

EXAMPLE 34B 6-(Phenylethynyl)-2-naphthalenecarboximidamidemono(trifluoroacetate) salt

The title compound was piepai-ed Irom Example 34A and the procedure ofExample 1B.

¹H NMR (300 MHz, DMSO-d₆) δ 7.49 (t, 3H), 7.62 (m, 2H), 7.80 (dd, 1H),7.86 (dd, 1H), 8.15 (d, 1H), 8.19 (d, 1H), 8.38 (s, 1H), 8.52 (s, 1H),9.38 (br s, 4H); MS (DCI/NH₃) m/e 271 (M+H)⁺. Anal. calcd forC₁₉H₁₄N₂.TFA: C, 65.62; H, 3.93; N, 7.29. Found: C, 65.64; H, 4.11; N,7.21.

EXAMPLE 353-Amino-N-[3-[6-(aminoiminomethyl)-2-naphthalenyl]-2-propynyl]benzamidemono(trifluoroacetate) salt EXAMPLE 35A6-(3-Amino-1-propynyl)-2-naphthalenecarbonitrile

The title compound was obtained from Example 28B, propargyl amine andthe procedure of Example 41A.

MS (DCI/NH₃) m/e 207 (M+NH₄)⁺.

EXAMPLE 35B 3-Amino-N-[3-(6-cyano-2-naphthalenyl)-2-propynyl]benzamide

A solution of Example 35A (100 mg, 0.49 mmole), 3-aminobenzoic acid (73mg, 0.53 mmole), EDC (141 mg, 0.74 mmole) and DMAP (89 mg, 0.74 mmole),in THF (5.5 mL) was stirred at room temperature for 2.5 h andconcentrated. The residue was dissolved in methylene chloride, washedwith 1N HCl, water, saturated NaHCO₃, and brine, dried (MgSO₄),concentrated and purified by flash chmomatography on silica gel with 2%ethanol/methylene chloride to provide the title compound.

MS (DCI/NH₃) m/e 326 (M+H)⁺.

EXAMPLE 35C3-Amino-N-[3-[6-(aminoiminomethyl)-2-naphthalenyl]-2-propynyl]benzamidemono(trifluoroacetate) salt

The title compound was prepared from Example 35B and the procedure ofExample 1B.

¹H NMR (300 MHz, DMSO-d₆) δ 4.32 (d, 2H), 5.69 (br s, 2H), 6.58 (d, 2H),7.62 (m, 3H), 7.82 (d, 1H), 8.08 (d, 1H), 8.14 (d, 1H), 8.20 (s, 1H),8.43 (s, 1H), 8.60 (t, 1H), 9.19 (br s, 2H), 9.42 (br s, 2H); MS(DCI/NH₃) m/e 343 (M+H)⁺. Anal. calcd for C₂₁H₁₈N₄O.TFA.0.25H₂O: C,59.93; H, 4.26; N, 12.16. Found: C, 59.86; H, 3.97; N, 11.93.

EXAMPLE 364-Amino-N-[3-(6-aminoiminomethyl-2-naphthalenyl)-2-propynyl]benzamidemono(trifluoroacetate) salt EXAMPLE 36A4-Amino-N-[3-(6-cyano-2-naphthalenyl)-2-propynyl]benzamide

Example 35A and 4-aminobenzoic acid were subjected to the conditionsdescribed in Example 35B to afford the title compound.

MS (DCI/NH₃) m/e 326 (M+H)⁺.

EXAMPLE 36B4-Amino-N-[3-(6-aminoiminomethyl-2-naphthalenyl)-2-propynyl]benzamidemono(trifluoroacetate) salt

The title compound was prepared from Example 36A and the procedure ofExample 5B.

¹H NMR (300 MHz, DMSO-d₆) δ 4.38 (d, 2H), 6.89 (m, 1H), 7.20 (m, 2H),7.22 (s, 1H), 7.63 (dd, 1H), 7.82 (dd, 1H), 8.09 (d, 1H), 8.12 (d, 1H),8.20 (s, 1H), 8.46 (s, 1H), 8.95 (t, 1H), 9.19 (br s, 2H), 9.42 (br s,2H); MS (DCI/NH₃) m/e 343 (M+H)⁺. Anal. calcd for C₂₁H₁₆N₄O.2.5TFA: C,49.27; H, 3.19; N, 8.54. Found: C, 49.27; H, 3.33; N, 8.89.

EXAMPLE 37(S)-2-Amino-N-[1-[(6-aminoiminomethyl-2-naphthalenyl)carbonyl]cyclohexyl]propionamidebis(trifluoroacetate) salt EXAMPLE 37A6-[(1-Aminocyclohexyl)ethynyl]-2-naphthalenecarbonitrile

The title compound was obtained from Example 28B,1-ethynylcyclohexylamine and the procedure of Example 41A.

MS (DCI/NH₃) m/e 275 (M+NH₄)⁺.

EXAMPLE 37B(S)-2-Amino-N-[1-[(6-cyano-2-naphthalenyl)carbonyl]cyclohexyl]propionamide

Example 37A and N-(t-butoxycarbonyl)-L-alanine were subjected to theconditions described in Example 35B to provide the title compound.

MS (DCI/NH₃) m/e 446 (M+H)⁺.

EXAMPLE 37C(S)-2-Amino-N-[1-[(6-aminoiminomethyl-2-naphthalenyl)carbonyl]cyclohexyl]propionamidebis(trifluoroacetate) salt

The title compound was a rearrangement product of Example 37B resultingfrom the procedure of Example 5B.

¹H NMR (300 MHz, DMSO-d₆) δ 1.24 (d, 3H), 1.40-1.62 (m, 8H), 2.15-2.26(s, 1H), 2.29-2.38 (s, 1H), 3.51 (d, 1H), 3.78 (d, 1H), 3.82 (s, 1H),7.90 (dd, 2H), 8.09 (dd, 1H), 8.18 (d, 1H), 8.37 (d, 1H), 8.55 (s, 1H),8.78 (s, 1H), 9.31 (s, 2H), 9.50 (s, 2H); MS (DCI/NH₃) m/e 381 (M+H)⁺.Anal. calcd for C₂₃H₂₈N₄O₂.2TFA.2H₂O: C, 49.39; H, 5.22; N, 8.53. Found:C, 49.15; H, 4.79; N, 8.70.

EXAMPLE 38 6-methoxy-8-benzyloxy-2-naphthalenecarboximidamidemono(trifluoroacetate) salt EXAMPLE 38A8-Hydroxy-6-methoxy-3,4-dihydro-2H-naphthalen-1-one

A solution of 6,8-dimethoxy-3,4-dihydro-2H-naphthalen-1-one (15 g, 72.8mmole), prepared according to the procedure of J. Chem. Soc., London2782 (1955), which is incorporated herein by reference, in methylenechloride (150 mL) at 0° C. was treated portionwise with AlCl₃ (14.3 g,107 mmole), stirred for 20 h at room temperature, poured onto ice withstirring and extracted with methylene chloride when the ice melted. Theextracts were washed with water and brine, dried (MgSO₄) andconcentrated to provide 13.8 g of the title compound.

MS (DCI/NH₃) m/e 193 (M+H)⁺.

EXAMPLE 38B 8-Benzyloxy-6-methoxy-3,4-dihydro-2H-naphthalen-1-one

A mixture of Example 38A (2.5 g, 13 mmole), benzyl bromide (2.1 mL, 17.8mmole), K₂CO₃ powder (14.3 g, 100 mmole), and 2-butanone (88 mL) wasstirred at reflux for 4 h, treated with additional benzyl bromide (1.0mL, 8.5 mmole), stirred at reflux for an additional 3 h, cooled to roomtemperature, filtered and concentrated. The residue was dissolved inmethylene chloride, washed with 1N HCl, water and brine, dried (MgSO₄)and concentrated. The crude product was purified on silica gel with 30%ethyl acetate/hexanes to provide the title compound.

MS (DCI/NH₃) m/e 283 (M+H)⁺.

EXAMPLE 38C3,4-Dihydro-2-(hydroxymethylene)-6-methoxy-8-(phenylmethoxy)-1(2H)-naphthalenone

Sodium metal (1.29 g, 55.9 mmole) was added portionwise to a mixture ofethanol (4.2 mL) and benzene (15 mL). The mixture was stirred at relluxfor 1.5 h, cooled to 0° C. and treated dropwise with ethyl formate (5.6mL, 70 mmole) then dropwise with of a solution of Example 38B (6.7g,23.8 mmole) in benzene (20 mL), stirred at room temperature for 2 h,cooled to 0° C., treated sequentially with ice/water and 6N HCl (75 mL)and extracted with ethyl acetate. The extracts were washed with brine,dried (MgSO₄) and concentrated to provide the title compound.

MS (DCI/NH₃) m/e 311 (M+H)⁺.

EXAMPLE 38D4,5-Dihydro-7-methoxy-9-(phenylmethoxy)naphth[2,1-d]isoxazole[2,1-d]isoxazole

A suspension of Example 38C (7.5 g, 24.3 mmole), hydroxylaminehydrochloride (4.0 g, 57.6 mmole) and acetic acid (63 mL) was stirred at110° C. for 7 min, cooled to room temperature, diluted with water andextracted with methylene chloride. The extracts were washed with waterand brine, dried (MgSO₄), and concentrated. The crude product waspurified by flash chromatography on silica gel with 30% ethylacetate/hexanes to provide the title compound.

MS (DCI/NH₃) m/e 308 (M+H)⁺.

EXAMPLE 38E 8-Benzyloxy-2-cyano-6-methoxy-3,4-dihydronaphthalen-1-one

Sodium methoxide, prepared from sodium metal (0.17 g, 7.35 mmol) inmethanol (3.9 mL), was treated dropwise with a solution of Example 38D(1.5 g, 4.9 mmole) in benzene (50 mL), stirred at room temperature for4.5 h, treated sequentially with water and 1N HCl and extracted withethyl acetate. The extracts were washed with brine, dried (MgSO₄) andconcentrated to provide the title compound.

MS (DCI/NH₃) m/e 308 (M+H)⁺.

EXAMPLE 38F 2-Cyano-6-methoxy-8-Benzyloxy-3,4-dihydronaphthalene

A suspension of Example 38E (2.6 g, 8.6 mmole) in absolute ethanol (25mL) at room temperature was treated portionwise with NaBH₄ (1.6 g),stirred for 20 min at room temperature and for 20 min at reflux, cooledto room temperature, treated with water (20 mL) and concentrated. Theresidue was dissolved in methylene chloride, washed with water andbrine, dried (MgSO₄), filtered and concentrated to provide 2.6 g of anorange foam. The foam was stirred at reflux for 20 min withp-toluenesulfonic acid monohydrate (0.52 g, 2.7 mmole) in benzene (52mL), cooled to room temperature, diluted with ethyl acetate, washed withwater and brine, dried (MgSO₄) and concentrated to provide the titlecompound.

MS (DCI/NH₃) m/e 309 (M+NH₄)⁺.

EXAMPLE 38G 2-Cyano-6-methoxy-8-benzyloxynaphthalene

A solution of Example 38F (0.4 g, 1.4 mmole),2,3-dichloro-5,6-dicyano-1,4-benzoquinone (0.79 g, 3.5 mmole) in benzene(40 mL) was stirred at reflux for 4 hours, treated with additional2,3-dichloro-5,6-dicyano-1,4-benzoquinone (0.4 g, 1.8 mmole), stirred atreflux for an additional 5 h, cooled to room temperature, diluted withethyl acetate, washed with saturated NaHCO₃ and brine, dried (MgSO₄) andconcentrated to provide the title compound.

MS (DCI/NH₃) m/e 290 (M+H)⁺.

EXAMPLE 38H 8-Benzyloxy-6-methoxy-2-naphthalenecarboximidamidemono(trifluoroacetate) salt

The title compound was prepared from Example 38G and the procedure ofExample 1B.

¹H NMR (300 MHz, DMSO-d₆) δ 4.38 (d, 2H), 6.89 (m, 1H), 7.20 (m, 2H),7.22 (s, 1H), 7.63 (dd, 1H), 7.82 (dd, 1H), 8.09 (d, 1H), 8.12 (d, 1H),8.20 (s, 1H), 8.46 (s, 1H), 8.95 (t, 1H), 9.19 (br s, 2H), 9.42 (br s,2H); MS (DCI/NH₃) m/e 307 (M+H)⁺. Anal. calcd for C₁₉H₁₈N₂O₂.TFA: C,60.00; H, 4.56; N, 6.66. Found: C, 59.93; H, 4.46; N, 6.51.

EXAMPLE 39 2-[(7-Aminoiminomethyl-3-methoxy-1-naphthalenyl)oxy]acetamidemono(trifluoroacetate) salt EXAMPLE 39A6-Methoxy-8-hydroxy-2-naphthalenecarbonitrile

A mixture of Example 38G (1.62 g, 5.6 mmole) and 10% dry Pd/C (0.50 g)in methanol (150 mL) was hydrogenated in a Parr shaker at roomtemperature under 4 atm for 30 h. The mixture was filtered andconcentrated to provide the title compound.

MS (DCI/NH₃) m/e 217 (M+NH₄)⁺.

EXAMPLE 39B 2-[(7-Cyano-3-methoxy-1-naphthalenyl)oxy]acetamide

Example 39A and 2-bromoacetamide were subjected to the conditionsdescribed in Example 5A to provide the title compound.

MS (DCI/NH₃) m/e 274 (M+NH₄)⁺.

EXAMPLE 39C2-[(7-Aminoiminomethyl-3-methoxy-1-naphthalenyl)oxy]acetamidemono(trifluoroacetate) salt

The title compound was prepared from Example 39B and the procedure ofExample 1B.

¹H NMR (300 MHz, DMSO-d₆) δ 3.93 (s, 3H), 4.70 (s, 2H), 6.70 (d, 1H),7.09 (d, 1H), 7.65 (s, 2H), 7.82 (dd, 1H), 7.99 (d, 1H), 8.70 (s, 1H),9.05 (s, 2H), 9.38 (s, 2H); MS (DCI/NH₃) m/e 274 (M+H)⁺. Anal. calcd forC₁₄H₁₅N₃O₃.TFA: C, 49.62; H, 4.16; N, 10.85. Found: C, 49.68; H, 4.24;N, 10.61.

EXAMPLE 40 N-(6-aminoiminomethyl-2-naphthalenyl)-N′-phenylureamono(trifluoroacetate) salt EXAMPLE 40A 6-Cyano-2-naphthalenecarbonylchloride

A suspension Example 8E (4.4 g, 22.3 mmol) in toluene (100 mL) wastreated with thionyl chloride (6.0 mL) and DMAP (5 mg), heated at 55° C.for 1 h, treated with additional thionyl chloride (3 mL), warmed to 95°C. for 1 h, cooled to room temperature, stirred in hexane (75 mL) for2.5 h and triturated to provide 3.62 of the title compound as a whitepowder. The filtrate was concentrated and triturated with ether toprovide an additional 1.02 g of the title compound.

MS (DCI/NH₃) m/e 215 (M+H)⁺.

EXAMPLE 40B 2-Cyano-6-naphthoyl azide

A solution of Example 40A (1.65 g, 7.65 mmole) in acetone (600 mL) atroom temperature was treated with a solution of sodium azide (3 g, 46mmole) in water (10 mL), stirred for 1.5 h and diluted with water (60mL). The resulting solid was filtered, washed with water and dried toprovide 4.24 g of the title compound as a white powder.

MS (DCI/NH₃) m/e 240 (M+NH₄)⁺.

EXAMPLE 40C N-(6-cyano-2-naphthalenyl)-N′-phenylurea

A solution of Example 40B (221.2 mg, 1 mmole) in toluene (18 mL) washeated at 85 ° C. for 1 h then at 95° C. for 1.5 h, cooled to roomtemperature, treated with aniline (240 μL, 2.63 mmole), stirred for 25min and treated with ether (10 mL). The resulting solid was collected,washed with ether and dried under vactiuim to yield 230 mg of whitepowder.

MS (DCI/NH₃) m/e 305 (M+NH₄)⁺.

EXAMPLE 40D N-(6-aminoiminomethyl-2-naphthalenyl)-N′-phenylureamono(trifluoroacetate) salt

A solution of Example 40C (148 mg, 0.5 mmole) in 10:1pyridine:triethylamine (10 mL) was treated with H₂S for 5 min, stirredat room temperature for 18 h and concentrated. The resulting solid wasdissolved in acetone (15 mL), treated with iodomethane (0.8 mL, 12.8mmole), stirred for 2 h, diluted with ether (10 mL), filtered, washedwith ether and dried under vacuum. The resulting solid was dissolved inmethanol, treated with 2N NH₃ in methanol (2 mL), warmed to 50° C. for 4h and concentrated. The product was purified according to the proceduredescribed in Example 1B to provide 62 mg of the title compound.

¹H NMR (300 MHz, DMSO-d₆) δ 7.00 (t, 1H), 7.31 (dd, 2H), 7.52 (d, 1H),7.65 (dd, 1H), 7.76 (dd, 1H, 8.02 (d, 2H), 8.30 (s, 1H), 8.39 (s, 1H),9.05 (br, s 2H), 9.11 (s, 1H), 9.33 (br s, 2H), 9.42 (s, 1H); MS(DCI/NH₃) m/e 305 (M+H)⁺; Anal. calcd for C₁₈H₁₆N₄O.TFA: C, 57.42; H,4.10; N, 13.39. Found: C, 57.50; H, 4.05; N, 13.08.

EXAMPLE 41 (E)-6-[2-(Phenyl)ethenyl]-2-naphthalenecarboximidamidemono(trifluoroacetate) salt EXAMPLE 41A(E)-6-[2-(Phenyl)ethenyl]-2-naphthalenecarbonitrile

A solution of Example 28B (350 mg, 1.16 mmol), styrene (157 mg, 1.51mmol), palladium (II) acetate (26 mg, 0.12 mmol), triphenylphosphine (61mg, 0.23 mmol), triethylamine (2 mL) and acetonitrile (1 mL) in a sealedtube with minimal head volume was heated at 100° C. for 19 h, dilutedwith ethyl acetate (20 mL), washed with water, dried (MgSO₄) andconcentrated with silica gel (4 g). The mixture was chromatographed onsilica gel with 10% ethyl acetate/hexane to provide 160 mg of the titlecompound.

MS (DCI/NH₃) m/e 273 (M+NH₄)⁺.

EXAMPLE 41B (E)-6-[2-(Phenyl)ethenyl]-2-naphthalenecarboximidamidemono(trifluoroacetate) salt

The title compound was prepared from Example 41A from the procedure ofExample 1B.

¹H NMR (300 MHz, DMSO-d₆) δ 7.33 (t, 1H), 7.4 (t, 2H), 7.5 (d, 2H), 7.69(d, 1H), 7.70 (d, 1H), 7.81 (dd, 1H), 8.03 (dd, 1H), 8.10 (d, 1H), 8.13(d, 1H), 8.17 (s, 1H), 8.44 (s, 1H), 8.97 (s, 2H), 9.41 (s, 2H); MS(DCI/NH₃) m/e 273 (M+H)⁺; Anal. calcd for C₁₉H₁₆N₂.TFA: C, 65.28; H,4.43; N, 7.25. Found: C; 64.95; H, 4.60; N, 6.42.

EXAMPLE 42 6-[2-(Phenyl)ethyl]-2-naphthalenecarboximidamidemono(trifluoroacetate) salt EXAMPLE 42A6-[2-(Phenyl)ethyl]-2-naphthalenecarbonitrile

A mixture of Example 57B (80 mg, 0.31 mmol) and palladium on carbon (20%water, 50 mg) in methanol (5 mL) was stirred under 1 atm of hydrogen for0.5 h, filtered and concentrated to provide 72 mg of the title compound.

MS (DCI/NH₃) m/e 275 (M+NH₄)⁺.

EXAMPLE 42B 6-[2-(Phenyl)ethyl]-2-naphthalenecarboximidamidemono(trifluoroacetate) salt

The title compound was prepared from Example 42A and the procedure ofExample 1B.

¹H NMR (300 MHz, DMSO-d₆) δ 3.03 (m, 2H), 7.23 (m, 5H), 7.60 (dd, 1H),7.76 (dd, 1H), 7.85 (s, 1H), 8.03 (t, 2H), 8.42 (s, 1H), 8.99 (s, 2H),9.39 (s, 2H); MS (DCI/NH₃) m/e 275 (M+H)⁺. Anal. calcd forC₁₉H₁₈N₂O.1.33TFA: C, 61.29; H, 4.59; N, 6.61. Found: C; 61.56; H, 4.62;N, 5.21.

EXAMPLE 43 7-Propoxy-8-iodo-2-naphthalenecarboximidamidemono(trifluoroacetate) salt EXAMPLE 43A7-propoxy-8-iodo-2-naphthalenecarbonitrile

Example 53A (65 mg, 0.25 mmol) in DMF (2 mL) was treated with propyliodide (40 mL), stirred at 65° C. for 1 h, diluted with water andextracted with diethyl ether. The organic extracts were dried (MgSO₄)and concentrated, and the residue was purified on silica gel with 10%ethyl acetate/hexanes to provide 160 mg of the title compound.

MS (DCI/NH₃) m/e 355 (M+H)⁺.

EXAMPLE 43B 7-Propoxy-8-iodo-2-naphthalenecarboximidamidemono(trifluoroacetate) salt

The title compound was prepared from the product in Example 43Aaccording to the procedure of Example 1B.

¹H NMR (300 MHz, DMSO-d₆) δ 1.09 (t, 3H), 1.82 (m, 2H), 4.23 (t, 2H),7.62 (d, 1H), 7.65 (dd, 1H), 8.12 (dd, 2H), 9.15 (s, 2H), 9.42 (s, 1H),9.53 (s, 2H); MS (DCI/NH₃) m/e 355 (M+H)⁺. Anal. calcd. forC₁₄H₁₅N₂OI.TFA.0.26C₇H₈: C, 43.49; H, 3.70; N, 5.69. Found: C; 43.50; H,3.59; N, 5.75.

EXAMPLE 44 (±)-6-(3-Phenyloxiranyl)-2-naphthalenecarboximidamidemono(trifluoroacetate) salt EXAMPLE 44A(±)-6-(3-Phenyloxyranyl)-2-naphthalenecarbonitrile

A solution of Example 41A (69 mg, 0.27 mmol) and m-chloroperbenzoic acid(70 mg, 0.41 mmol) in methylene chloride (3 mL) was stirred at 25° C.for 3 days, concentrated, loaded on a silica gel column (pretreated with0.1% triethylamine in ethyl acetate) and eluted with 10% ethylacetate/hexane) to provide 72 mg of the title compound.

MS (DCI/NH₃) m/e 289 (M+NH₄)⁺.

EXAMPLE 44B (±)-6-(3-Phenyloxiranyl-2-naphthalenecarboximidamidemono(trifluoroacetate) salt

The title compound was prepared with Example 44A from the procedure ofExample 1B.

¹H NMR (300 MHz, DMSO-d₆) δ 4.24 (d, 1H), 4.35 (d, 1H), 7.43 (m, 5H),7.67 (dd, 1H), 7.83 (dd, 1H), 8.12 (s, 1H), 8.13 (d, 1H), 8.16 (d, 1H),8.50 (s, 1H), 9.03 (s, 2 H), 9.44 (s, 2H); MS (DCI/NH₃) m/e 289 (M+H)⁺.Anal. calcd for C₁₉H₁₆N₂O.1.3 TFA: C, 64.52; H, 4.55; N, 6.51. Found: C;64.35; H, 4.60; N, 5.87.

EXAMPLE 45 (E)-6-[2-(2-Thienyl)ethenyl]-2-naphthalenecarboximidamidemono(tifluoroacetate) salt EXAMPLE 45A 2-Vinylthiophene

A suspension of methyltriphenylphosphonium bromide (19.13 g, 53.5 mmol)in THF (100 mL) was treated dropwise with 2M butyllithium in THF (17.8mL) then dropwise with 2-carboxythiophene (5 g, 44.6 mmol), stirred for30 min then distilled at 74-78° C. to provide the title compound.

MS (DCI/NH₃) m/e 111 (M+H)⁺.

EXAMPLE 45B (E)-6-[2-(2-Thienyl)ethenyl]-2-naphthalenecarbonitrile

The title compound was prepared from the product of Example 45A and theprocedure of Example 41A.

MS (DCI/NH₃) m/e 279 (M+NH₃)⁺.

EXAMPLE 45C (E)-6-[2-(2-Thienyl)ethenyl]-2-naphthalenecarboximidamidemono(trifluoroacetate) salt

The title compound was prepared from Example 45B and the procedure ofExample 1B.

¹H-NMR (300 MHz, DMSO-d₆) δ 7.12 (dd, 2H), 7.15 (d, 1H), 7.32 (d, 1H),7.6 (d, 1H), 7.74 (d, 1H), 7.80 (dd, 1H), 7.9-8.1 (m, 3H), 8.14 (s, 1H),8.43 (s, 1H), 9.03 (s, 2H), 9.42 (s, 2H); MS (DCI/NH₃) m/e 279 (M+H)⁺;Anal. calcd. for C₁₇H₁₄N₂O₂S.TFA: C, 53.77; H, 3.56; N, 6.60. Found: C;54.88; H, 3.66; N, 6.45.

EXAMPLE 46 6-(3-Oxobutyl)-2-naphthalenecarboximidamidemono(trifluoroacetate) salt EXAMPLE 46A6-(3-Oxobutyl)-2-naphthalenecarbonitrile

The title compound was prepared from Example 28B, 1-buten-3-ol and theprocedure of Example 41A.

MS (DCI/NH₃) m/e 241 (M+NH₄)⁺.

EXAMPLE 46B 6-(3-Oxobutyl)-2-naphthalenecarboximidamidemono(trifluoroacetate) salt

The title compound was prepared from Example 46A and the procedure ofExample 1B.

¹H NMR (300 MHz, DMSO-d₆) δ 2.13 (s, 1H), 2.94 (m, 4H), 7.57 (dd, 1H)7.78 (dd, 1H), 7.85 (s, 1H), 8.01 (d, 1H), 8.05 (d, 1H), 8.43 (s, 1H),8.48 (m, 2H), 9.06 (s, 2H), 9.40 (s, 2H); MS (DCI/NH₃) m/e 241 (M+H)⁺;Anal. calcd. for C₁₅H₁₆N₂O.1.3TFA: C, 54.31; H, 4.48; N, 7.19. Found: C;54.33; H, 4.35; N, 7.27.

EXAMPLE 47 6-(3-Methoxyphenyl)-2-naphthalenecarboximidamidemono(trifluoroacetate) salt EXAMPLE 47A6-(3-Methoxyphenyl)-2-naphthalenecarbonitrile

A solution of Example 28B (300 mg, 1 mmol), palladium (II) acetate (22mg, 0.1 mmol) and 1-1′-bis(diphenyphosphino)ferrocene (111 mg, 0.2 mmol)was stirred in DMF (3 mL) for 15 min, treated with Cs₂CO₃ (813 mg, 2.5mmol) and 3-methoxyphenylboronic acid (228 mg, 1.5 mmol), stirred for 20min at 80° C., cooled, treated with pH 7 buffer (10 mL) and extractedwith diethyl ether. The ether extracts were dried (MgSO₄), concentratedand purified on silica gel with 10% ethyl acetate/hexane to provide 140mg of the title compound as a white solid.

MS (DCI/NH₃) m/e 277 (M+NH₄)⁺.

EXAMPLE 47B 6-(3-Methoxyphenyl)-2-naphthalenecarboximidamidemono(trifluoroacetate) salt

The title compound was prepared from Example 47A and the procedure ofExample 1B.

¹H NMR (300 MHz, DMSO-d₆) δ 3.88 (s, 3H), 7.03 (m, 1H), 7.44 (m, 3H),7.84 (dd, 1H),8.05 (dd, 1H), 8.19 (d, 1H), 8.21 (d, 1H), 0.41 (s, 1H),8.51 (s, 1H), 9.11 (s, 2H), 9.45 (s, 2H); MS (DCI/NH₃) m/e 277 (M+H)⁺;Anal. calcd for C₁₈H₁₆N₂O.TFA.0.2H₂O: C, 61.03; H, 4.45; N, 7.12. Found:C; 61.03; H, 4.11; N, 6.86.

EXAMPLE 48N-[3-(methyl)phenyl]-6-aminoiminomethyl-2-naphthalenecarboxamidemono(trifluoroacetate) salt EXAMPLE 48AN-[3-(methyl)phenyl]-6-cyano-2-naphthalenecarboxamide

The title compound was prepared from 3-methyl phenylisocyanate, Example55C and the procedure from Example 55C.

MS (DCI/NH₃) m/e 287 (M+H)⁺.

EXAMPLE 48BN-[3-(methyl)phenyl]-6-aminoiminomethyl-2-naphthalenecarboxamidemono(trifluoroacetate) salt

The title compound was prepared from Example 48A and the procedure ofExample 1B.

¹H NMR (300 MHz, DMSO-d₆) δ 2.34 (s, 3H), 6.96 (d, 1H), 7.27 (t, 1H),7.62 (d, 1H), 7.66 (s, 1H), 7.91 (dd, 1H), 8.15 (dd, 1H), 8.29 (d, 1H),8.31 (d, 1H), 8.54 (s, 1H), 8.68 (s, 1H), 9.15 (s, 2H), 9.49 (s, 2H),10.46 (s, 1H); MS (DCI/NH₃) m/e 304 (M+H)⁺; Anal. calcd forC₁₉H₁₇N₃O.TFA.0.12C₇H₈: C, 61.23; H, 4.46; N, 9.81. Found: C; 61.12; H,4.42; N, 9.43.

EXAMPLE 49 6-(2-Formylphenoxy)-2-naphthalenecarboximidamidemono(trifluoroacetate) salt EXAMPLE 49A6-(2-Formylphenoxy)-2-naphthalenecarbonitrile

A solution of 2-hydroxybenzaldehyde (72 mg, 0.59 mmol),6-bromo-1-cyanonaphthalene (150 mg, 0.65 mmol), and Cs₂CO₃ (248 mg, 0.76mmol) in DMF (10 mL) was heated at 90° C. for 2 days, treated with waterand extracted with ethyl acetate. The combined organic extracts weredried (MgSO₄) and concentrated, and the crude product was purified bycolumn chromatography with 10% ethyl acetate/hexane to provide 40 mg ofthe title compound.

MS (DCI/NH₃) m/e 291 (M+NH₄)⁺.

EXAMPLE 49B

6-(2-Formylphenoxy)-2-naphthalenecarboximidamide mono(trifluoroacetate)salt

The title compound was prepared with Example 49A and the procedure ofExample1B.

¹H-NMR (300 MHz, DMSO-d₆) δ 7.19 (d, 1H), 7.44 (t, 1H), 7.56 (s, 1H),7.60 (d, 1H), 7.79 (m, 2H), 7.94 (dd, 1H), 8.01 (d, 1H), 8.2 (d, 1H),8.51 (s, 1H), 9.03 (s, 2H), 9.41 (s, 2H), 10.35 (s, 1H); MS (DCI/NH₃)m/e 291 (M+H)⁺. Anal. calcd. for C₁₈H₁₄N₂O₂.TFA.1.7H₂O: C, 55.16; H,4.27; N, 6.43. Found: C; 55.17; H, 3.92; N, 5.94.

EXAMPLE 50 6-(2-Formylphenyl)-2-naphthalenecarboximidamidemono(trifluoroacetate) salt EXAMPLE 50A6-(2-Formylphenyl)-2-naphthalenecarbonitrile

The title compound was prepared from Example 28B, 2-formylphenylboronicacid and the procedure of Example 47A.

MS (DCI/NH₃) m/e 275 (M+NH₄)⁺.

EXAMPLE 50B 6-(2-Formylphenyl)-2-naphthalenecarboximidamidemono(trifluoroacetate) salt

The title compound was prepared from Example 50A and the procedure ofExample 1B.

¹H NMR (300 MHz, DMSO-d₆) δ 7.71-7.64 (m, 2H), 7.79 (d, 1H), 7.81 (s,1H), 7.88 (dd, 1H), 7.9 (d, 1H), 8.16 (d, 1H), 8.23 (t, 2H), 8.56 (s,1H), 9.05 (s, 2H), 9.48 (s, 2H), 9.92 (s, 1H); MS (DCI/NH₃) m/e 275(M+H)⁺; Anal. calcd for C₁₈H₁₄N₂O.TFA: C, 61.86; H, 3.89; N, 7.21.Found: C; 61.98; H, 3.59; N, 6.88.

EXAMPLE 51 6-[2-(Hydroxymethyl)phenyl]-2-naphthalenecarboximidamidemono(trifluoroacetate) salt EXAMPLE 51A6-[2-(Hydroxymethyl)]-2-naphthalenecarbonitrile

Example 50A (98 mg, 0.38 mmol) and sodium borohydride (15 mg, 0.80 mmol)were dissolved in methanol (10 mL) and stirred for 0.5 h. The solutionwas concentrated, and the residue was purified on silica gel with 30%ethyl acetate/hexane to provide 90 mg of the title compound.

MS (DCI/NH₃) m/e 277 (M+NH₄)⁺.

EXAMPLE 51B 6-[2-(Hydroxymethyl)phenyl]-2-naphthalenecarboximidamidemono(trifluoroacetate) salt

The title compound was prepared from Example 51A and the procedure ofExample 1B.

¹H NMR (300 MHz, DMSO-d₆) δ 9.46 (s, 2H), 9.06 (s, 2H), 8.54 (s, 1H),8.16 (t, 2H), 8.07 (s, 1H), 7.85 (dd, 1H), 7.74 (dd, 1H), 7.63 (d, 1H),7.49-7.34 (m, 3H), 4.46 (s, 2H); MS (DCI/NH₃) m/e 277 (M+H)⁺; Anal.calcd. for C₁₈H₁₆N₂O.1.44TFA: C, 56.93; H, 3.99; N, 6.36. Found: C;56.94; H, 3.88; N, 6.46.

EXAMPLE 52 6-(3-Oxo-1-butenyl)-2-naphthalenecarboximidamidemono(trifluoroacetate) salt EXAMPLE 52A6-(3-Oxo-1-butenyl)-2-naphthalenecarbonitrile

The title compound was prepared from methyl acrylate, Example 28B andthe procedure of Example 41A. MS (DCI/NH₃) m/e 222 (M+H)⁺.

EXAMPLE 52B 6-(3-Oxo-1-butenyl)-2-naphthalenecarboximidamidemono(trifluoroacetate) salt

The title compound was prepared from Example 52A and the procedure ofExample 1B.

¹H NMR (300 MHz, DMSO-d₆) δ 9.46 (s, 2H), 9.13 (s, 2H), 8.48 (s, 1H),8.38 (s, 1H), 8.18 (d, 1H), 8.15 (d, 1H), 8.01 (dd, 1H), 7.85 (dd, 1H),7.82 (d, 1H), 7.03 (d, 1H), 2.40 (s, 1H); MS (DCI/NH₃) m/e 239 (M+H)⁺.Anal. calcd for C₁₅H₁₄N₂O.1.58TFA: C, 52.13; H, 3.75; N, 6.69. Found: C;52.09; H, 3.63; N, 6.64.

EXAMPLE 53 7-Methoxy-8-(1H-pyrazol-4-yl)-2-naphthalenecarboximidamidebis(trifluoroacetate) salt EXAMPLE 53A7-hydroxy-8-iodo-2-naphthalenecarbonitrile

A mixture of 7-cyano-2-naphthol (22.3 g, 131.8 mmol), sodium carbonate(29.3 g, 277 mmol) and I₂ (31.8 g, 125.2 mmol) in water (500 mL) and THF(80 mL) at 0° C. was stirred at room temperature for 3 h, acidified with1M HCl and extracted with ethyl acetate. The extracts were washed withsaturated Na₂S₂O₃ and brine, dried (Na₂SO₄) and concentrated. Theproduct was recrystallized from ethyl acetate to yield 33 g of the titlecompound.

MS (DCI/NH₃) m/e 313 (M+NH₄)⁺.

EXAMPLE 53B 7-Methoxy-8-iodo-2-naphthalenecarbonitrile

Example 53A (36.7 g, 124.2 mmol) in methanol (500 mL) and ethyl acetate(300 mL) was treated over 3 h with 2M trimethylsilyldiazomethane inhexane (260 mL), stirred for 24 h, concentrated and recrystallized fromethyl acetate to provide 36.4 g of the title compound.

MS (DCI/NH₃) m/e 327 (M+NH₄)⁺.

EXAMPLE 53C 4-Iodo-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-pyrazole

A slurry of NaH (1.94 g, 48.5 mmol) in THF (40 mL) at 0° C. was treatedwith a solution of 4-iodopyrazole (8.97 g, 46.2 mmol) in THF (20 mL),stirred for 1 h, treated with SEM chloride (9.00 mL, 50.8 mmol), stirredat room temperature for 1 h, poured into water and extracted with ethylacetate. The extracts were washed with brine, dried (MgSO₄) andconcentrated. The residue was chromatographed on silica gel with 10%ethyl acetate/hexanes to provide 14.4 g of the title compound.

MS (DCI/NH₃) m/e 325 (M+H)⁺.

EXAMPLE 53D [1-[[2-(Trimethylsilyl)ethoxy]methyl]-1H-pyrazol4-yl]boronicacid

Example 53C (12.97 g, 40 mmol) in THF (250 mL) at −78° C. was treatedwith 2.5 M butyllithium in hexanes (17.6 mL, 44 mmol), stirred at −78°C. for 10 min, treated with trimethyl borate (11.36 mL, 100 mmol),warmed to room temperature, treated with 3M HCl (400 mL) and extractedwith ethyl acetate. The extracts were concentrated, and the residue wasdissolved in 1M NaOH (500 mL), extracted with diethyl ether, acidifiedwith concentrated HCl and extracted with ethyl acetate. The extractswere washed with brine, dried (Na₂SO₄), and concentrated. The residuewas chromatographed on silica gel with ethyl acetate to provide 2.20 gof the title compound.

MS (DCI/NH₃) m/e 199 (M-B(OH)₂)⁺.

EXAMPLE 53E7-Methoxy-8-[1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-pyrazol-4-yl]-2-naphthalenecarbonitrile

Examples 53B (1.55 g, 5 mmol) and 53D (1.45 g, 6 mmol) were subjected tothe procedure described in Example 47A to provide 1.64 g of the titlecompound.

MS (DCI/NH₃) m/e 380 (M+H)⁺.

EXAMPLE 53F 7-Methoxy-8-(1H-pyrazol-4-yl)-2-naphthalenecarbonitrile

A solution of Example 53E (1.84 g, 4.85 mmol) in THF (10 mL) was treatedwith 1M tetrabutylammonium fluoride in THF (24 mL), refluxed for 6 h andconcentrated. The residue was chromatographed on silica gel with 1:1ethyl acetate/hexanes to provide 0.88 g of the title compound.

MS (DCI/NH₃) m/e 267 (M+NH₄)⁺.

EXAMPLE 53G 7-Methoxy-8-(1H-pyrazol-4-yl)-2-naphthalenecarboximidamidebis(trifluoroacetate) salt

The title compound was prepared from Example 53F and the procedure ofExample 1B.

¹H NMR (300 MHz, DMSO-d₆) δ 3.89 (s, 3H), 7.60 (dd, 1H), 7.71 (d, 1H),7.92 (s, 2H), 8.05 (d, 1H), 8.12 (d, 1H), 8.29 (s, 1H), 9.33 (s, 2H),9.34 (s, 2H); MS (DCI/NH₃) m/e 267 (M+H)⁺; Anal. calcd. forC₁₅H₁₄N₄O.2.8TFA: C, 42.30; H, 2.90; N, 9.59. Found: C; 42.54; H, 3.11;N, 9.03.

EXAMPLE 54 7-Methoxy-8-iodo-2-naphthalenecarboximidamidemono(trifluoroacetate) salt

The title compound was prepared from Example 53B and the procedure ofExample 1B.

¹H NMR (300 MHz, DMSO-d₆) δ 4.01 (s, 3H), 7.65 (m, 2H), 8.12 (d, 1H),8.15 (d, 1H), 8.42 (s, 1H), 9.14 (s, 2H), 9.52 (s, 2H); MS (DCI/NH₃) m/e327 (M+H)⁺. Anal. calcd for C₁₂H₁₂N₂OI.1.2TFA: C, 37.28; H, 2.87; N,6.04. Found: C; 37.35; H, 2.47; N, 5.93.

EXAMPLE 55 N-phenyl-6-aminoiminomethyl-2-naphthalenecarboxamidemono(methanesulfonate) salt EXAMPLE 55A2-Trifluoromethanesulfonyloxy-6-bromonaphthalene

A solution of 6-bromo-2-naphthol (4.96 g, 22.25 mmol),N-phenyltrifluoromethanesulfonate (7.95 g, 22.25 mmol), anddiisopropylethylamine (7.75 mL, 44.5 mmol) in methylene chloride (25 mL)were stirred for 3 h at room temperature, poured into water andextracted with diethyl ether. The extracts were washed with brine, dried(MgSO₄), and concentrated. The residue was chromatographed on silica gelwith 3% ethyl acetate/hexane to provide 7.89 g of the title Compound.

MS (DCI/NH₃) m/e 354 and 356 (M+H)⁺.

EXAMPLE 55B 6-Bromo-2-naphthalenecarbonitrile

Example 55A (7.89 g, 22.2 mmol) was combined with Zn(CN)₂ (1.33 g, 11.33mmol) and Pd(PPh₃)₄ (256 mg, 0.22 mmol) in DMF (50 mL), heated at 90° C.for 3 h, cooled to room temperature, treated with saturated NaHCO₃ andextracted with diethyl ether. The extracts were washed with brine, driedover (MgSO₄), and condensed. The residue was chromatographed on silicagel with 5%, ethyl acetate/hexanes to provide 2.67 g of the titlecompound.

MS (DCI/NH₃) m/e 231 and 233 (M+H)⁺.

EXAMPLE 55C N-phenyl-6-cyano-2-naphthalenecarboxamide

A solution of Example 55B (224 mg, 0.965 mmol) in THF (3 mL) and hexanes(1 mL) at −100° C. was treated with 2.5 M butyllithium in hexanes (0.386mL, 0.965 mmol), stirred at −100° C. for 5 min, treated with phenylisocyanate (0.115 mL, 1.06 mmol), warmed to room temperature, treatedwith pH 7 buffer (0.5 mL) and concentrated. The residue waschromatographed on silica gel with 20% ethyl acetate/hexanes as eluent,to provide 54 mg of the title compound:

MS (DCI/NH₃) m/e 273 (M+H)⁺.

EXAMPLE 55D N-phenyl-6-aminoiminomethyl-2-naphthalenecarboxamidemono(methanesulfonate) salt

A solution of Example 55C (52 mg, 0.191 mmol) in THF (2 mL) was treatedwith 1M lithium bis(trimethylsilyl)amide in THF (0.6 mL), stirred for 18h, treated with 2M HCl (4 mL), stirred for another 24 h, made basic withsaturated Na₂CO₃ and extracted with ethyl acetate. The extracts werewashed with brine, dried (Na₂SO₄) and concentrated. The crude productwas dissolved into a minimal amount of methanol (ca. 1 mL), treated withmethanesulfonic acid (1 drop), diluted with diethyl ether (400 mL) andfiltered to provide 15 mg of the title compound.

¹H NMR (300 MHz, DMSO-d₆) δ 2.32 (s, 3H), 7.15 (dd, 1H), 7.40 (dd, 2H),7.83 (d, 2H), 7.90 (dd, 1H), 8.17 (dd, 1H), 8.25 (d, 1H), 8.34 (d, 1H),8.57 (s, 1H), 8.70 (s, 1H), 9.09 (br s, 2H), 9.51 (br s, 2H); MS(DCI/NH₃) m/e 290 (M+H)⁺. Anal. calcd for C_(18H) ₁₆N₃O.1.1 CH₃SO₃H: C,57.96; H, 4.95; N, 10.61. Found: C, 58.03; H, 4.48; N, 10.36.

EXAMPLE 564-[(6-Aminoiminomethyl-2-naphthalenyl)oxy]-N-methylbenzeneacetamidemono(trifluoroacetate) salt EXAMPLE 56AN-methyl-3-hydroxyphenylacetamide

A solution of 3-hydroxyphenylacetic acid (1.00 g, 6.57 mmol) and oxalylchloride (0.63 mL, 7.22 mmol) in methylene chloride (20 mL) was treateddropwise with pyridine (0.6 mL, 7.37 mmol), stirred for 90 min, pouredinto 40% aqueous methylamine (30 mL), stirred for 15 min, concentrated,dissolved into 1M HCl and extracted with ethyl acetate. The extractswere washed with brine, dried (MgSO₄) and concentrated. The residue waschromatographed on silica gel with ethyl acetate to provide 260 mg ofthe title compound.

MS (DCI/NH₃) m/e 166 (M+H)⁺.

EXAMPLE 56B 4-[(6-Cyano-2-naphthalene)oxy]-N-methylbenzeneacetamide

A mixture of Example 56A (245 mg, 1.48 mmol), Example 55B (344 mg, 1.48mmol) and Cs₂CO₃ (530 mg, 1.63 mmol) in DMF (3 mL) was stirred for 72 hat 120° C., cooled and chromatographed on silica gel with 1:1 ethylacetate/hexanes to provide 54 mg of the title compound.

MS (DCI/NH₃) m/e 317 (M+H)⁺.

EXAMPLE 56C4-[(6-Aminoiminomethyl-2-naphthalenyl)oxy]-N-methylbenzeneacetamidemono(trifluoroacetate) salt

The title compound was prepared from Example 56B and the procedure ofExample 55D.

¹H NMR (300 MHz, DMSO-d₆) δ 2.33 (s, 3H), 2.58 (d, 3H), 3.42 (s, 2H),7.05 (m, 2H), 7.12 (d, 1H), 7.40) (dd, 1H), 7.45 (m, 2H), 7.79 (dd, 1H),7.98 (q, 1H), 8.02 (d 1H), 8.15 (d, 1H), 8.49 (s, 1H), 8.99 (br s, 2H),9.39 (br s, 2H); MS (DCI/NH₃) m/e 334 (M+H)⁺. Anal. calcd forC₁₉H₁₇N₃O₂.1.5CH₃SO₃H: C, 54.08; H, 5.28; N, 8.80. Found: C, 53.80; H,5.37; N, 8.52.

EXAMPLE 57 6-[2-(Methylthio)phenyl]-2-naphthalenecarboximidamidemono(methanesulfonate) salt EXAMPLE 57A 2-Cyanonaphthalene-6-boronicacid

A solution of Example 55B (6.37 g, 27.45 mmol) in THF (220 mL) andhexanes (50 mL) at −100° C. was treated with 2.5 M butyllithium inhexanles (11.0 mL, 27.5 mmol), stirred at −100° C. for 10 min, treatedwith trimethyl borate (7.8 mL, 68.6 mmol), warmed to room temperature,treated with 3M HCl (400 mL) and extracted with ethyl acetate. Theextracts were concentrated and the residue was dissolved into 1M NaOH(500 mL), extracted with diethyl ether, acidified with 12M HCl andextracted with ethyl acetate. The extracts were washed with brine, dried(Na₂SO₄), and concentrated. The residue was dissolved into minimalmethanol and ethyl acetate and triturated with hexanes to yield 2.74 gof the title compound.

MS (DCI/NH₃) m/e 215 (M+NH₄)⁺.

EXAMPLE 57B 6[-2-(Methylthio)phenyl]-2-naphthalenecarbonitrile

A solution of 2-bromothioanisole (0.147 mL, 1.10 mmol), Pd(OAc)₂ (24 mg,0.11 mmol) and 1,1′-bis(diphenylphosphinoferrocene) (120 mg, 0.22 mmol)in DMF (5 mL) was stirred for 10 min, treated with Example 57A (260 mg,1.32 mmol) and Cs₂CO₃ (1.07 g, 3.3 mmol), heated at 85° C. for 6 h,cooled to room temperature and chromatographed on silica gel with 10%ethyl acetate/hexanes to provide 155 mg of the title compound.

MS (DCI/NH₃) m/e 231 (M+NH₄)⁺.

EXAMPLE 57C 6-[2-(Methylthio)phenyl]-2-naphthalenecarboximidamidemono(methanesulfonate) salt

The title compound was prepared from Example 57B and the procedure ofExample 55D.

¹H NMR (300 MHz, DMSO-d₆) δ 2.32 (s, 3H), 2.40 (s, 3H), 7.34 (m, 2H),7.45 (m, 2H), 7.82 (dd, 2H), 7.95 (dd, 1H), 8.06 (s, 1H), 8.15 (d, 1H),8.20 (d, 1H), 8.55 (s, 1H), 9.03 (br s, 2H), 9.56 (br s, 2H); MS(DCI/NH₃) m/e 293 (M+H)⁺. Anal. calcd for C₁₈H₁₇N₂S.CH₃SO₃H: C, 58.18;H, 5.18; N, 7.12. Found: C, 57.97; H, 5.31; N, 6.97.

EXAMPLE 586-[2-(2-Thiomethoxoxyethyl)phenyl]naphthalene-2-carboximidamidemono(methanesulfonate) salt EXAMPLE 58A 2-(2-Bromoethyl)bromobenzene

A solution of 2-bromophenethyl alcohol (5.05 g, 25.1 mmol) and pyridine(3.65 mL, 45.2 mmol) in acetonitrile (60 mL) was treated with Ph₃PBr₂(13.8 g, 32.65 mmol), stirred at 0° C. for 2 h, diluted with hexanes andfiltered through a plug of silica gel with 25% diethyl ether/hexanes toprovide 6.0 g of the title compound.

MS (DCI/NH₃) m/e 263 (M+H)⁺.

EXAMPLE 58B 2-(2-Thiomethoxyethyl)bromobenzene

A solution of Example 58A (990 mg, 3.75 mmol) and sodium thiomethoxide(290 mg, 4.12 mmol) in DMF (5 mL) was heated at 90° C. for 5 h, cooledand chromatographed on silica gel with 1% ethyl acetate/hexanes toprovide 646 mg of the title compound.

MS (DCI/NH₃) m/e 231, 233 (M+H)⁺.

EXAMPLE 58C 6-[2-(2-Thiomethoxyethyl)phenyl]-2-naphthalenecarbonitrile

The title compound was prepared from Example 58B (300 mg, 1.30 mmol),Example 57A (260 mg, 1.32 mmol) and the procedure described in Example57B.

MS (DCI/NH₃) m/e 321 (M+NH₄)⁺.

EXAMPLE 58D6-[2-(2-Thiomethoxoxyethyl)phenyl]naphthelene-2-carboximidamidemono(methanesulfonate) salt

The title compound was prepared from Example 58C and the procedure fromExample 55D.

¹H NMR (30 MHz, DMSO-d₆) δ 1.78 (s, 3H), 2.31 (s, 3H), 2.55 (m, 2H),2.85 (m, 2H), 7.30-7.48 (m, 4H), 7.66 (dd, 1H), 7.85 (dd, 1H), 8.04 (s,1H), 8.18 (d, 1H), 8.20 (d, 1H), 8.55 (s, 1H), 9.01 (br s, 2H), 9.43 (brs, 2H); MS (DCI/NH₃) m/e 321 (M+H)⁺. Anal. calcd forC₂₀H₂₀N₂S₂.1.35CH₃SO₃H: C, 56.96; H, 5.69; N, 6.22. Found: C, 57.08; H,5.49; N, 6.14.

EXAMPLE 59 7-Methoxy-8-(3-furanyl)-2-naphthalenecarboximidamidemono(methanesulfonate) salt EXAMPLE 59A7-Methoxy-8-(3-furanyl)-2-naphthalenecarbonitrile

The title compound was prepared from Example 53B, furan-3-boronic acid(873 mg, 7.80 mmol) and the procedure of Example 57B.

MS (DCI/NH₃) m/e 267 (M+NH₄)⁺.

EXAMPLE 59B 7-Methoxy-8-(3-furanyl)-2-naphthalenecarboximidamidemono(methanesulfonate) salt

The title compound was prepared from Example 58C and the procedure fromExample 55D.

¹H NMR (300 MHz, DMSO-d₆) δ 2.34 (s, 3H), 3.91 (s, 3H), 6.76 (s, 2H),7.62 (dd, 1H), 7.74 (d, I1H), 7.87 (dd, 1H), 7.96 (s, 1H), 8.12 (d, 1H),8.15 (d, 1H), 8.25 (s, 1H), 8.96 (br s, 2H), 9.35 (br s, 2H); MS(DCI/NH₃) m/e 267 (M+H)⁺. Anal. calcd for C₁₆H₁₄N₂O₂.CH₃SO₃H: C, 55.77;H, 5.00; N, 7.63. Found: C, 55.73; H, 4.61; N, 7.48.

EXAMPLE 60 7-Methoxy-8-(2-benzofuranyl)naphthalene-2-carboximidamidemono(methanesulfonate) salt EXAMPLE 60A7-Methoxy-8-(2-benzofuranyl)-2-naphthalenecarbonitrile

The title compound was prepared from Example 53B (166 mg, 0.50 mmol),benzofuran-2-boronic acid (113 mg, 0.70 mmol) and the procedure ofExample 57B.

MS (DCI/NH₃) m/e 317 (M+NH₄)⁺.

EXAMPLE 60B 7-Methoxy-8-(2-benzofuranyl)naphthalene-2-carboximidamidemono(methanesulfonate) salt

The title compound was prepared from Example 60A (72 mg, 0.240 mmol) andthe procedure from Example 55D.

¹H NMR (300 MHz, DMSO-d₆) δ 2.30 (s, 3H), 3.98 (s, 3H), 7.24 (s, 1H),7.36 (m, 2H), 7.67 (m, 2H), 7.75 (m, 1H), 7.84 (d, 1H), 8.21 (d, 1H),8.30 (d, 1H), 8.32 (s, 1H), 8.88 (br s, 2H), 9.39 (br s, 2H); MS(DCI/NH₃) m/e 317 (M+H)⁺. Anal. calcd for C₂₀H₁₆N₂O₂.1.3CH₃SO₃H: C,57.98; H, 4.84; N, 6.35. Found: C, 57.79; H, 4.78; N, 6.22.

EXAMPLE 61(E)-8-[2-(1,3-Benzodioxol-5-yl)ethenyl]-2-naphthalenecarboximidamidemono(metlhanesulfonate) salt EXAMPLE 61A(E)-8-[2-(1,3-Benzodioxol-5-yl)ethenyl]-2-naphthalenecarbonitrile

Example 53B (75 mg, 0.243 mmol), PdCl₂(dppf) (20 mg, 0.024 mmol),3,4-methylenedioxystyrene (43 mg, 0.291 mmol) and diisopropylethylamine(0.170 mL, 0.97 mmol) in N-methylpyrrolidinone (2 mL) were stirred at90° C. for 18 h, cooled to room temperature and chromatographed onsilica gel with 20% ethyl acetate/hexanes to provide 46 mg of the titlecompound.

MS (DCI/NH₃) m/e 347 (M+NH₄)⁺.

EXAMPLE 61B(E)-8-[2-(1,3-Benzodioxol-5-yl)ethenyl]-2-naphthalenecarboximidamidemono(methanesulfonate) salt

The title compound was prepared from Example 61A (43 mg, 0.131 mmol) andthe procedure from Example 55D.

¹H NMR (300) MHz, DMSO-d₆) δ 2.32 (s, 3H), 4.01 (s, 3H), 6.07 (s, 2H),6.96 (d, 2H), 7.10 (d, 2H), 7.32 (d, 2H), 7.45 (s, 1H), 7.56 (d, 1H),7.66 (d, 2H), 7.72 (d, 1H), 8.06 (s, 1H), 8.03 (d, 1H), 8.12 (d, 1H),8.66 (s, 1H), 8.96 (br s, 2H), 9.44 (br s, 2H); MS (DCI/NH₃) m/e 347(M+H)⁺. Anal. calcd for C₂₁H₁₈N₂O₃.1.1CH₃SO₃H: C, 58.72; H, 4.99; N,6.20. Found: C, 58.77; H, 5.07; N, 5.99.

EXAMPLE 62(±)-7-Methoxy-8-(tetrahydro-3-furanyl)-2-naphthalenecarboximidamidemono(methanesulfonate) salt EXAMPLE 62A(±)-7-methoxy-8-[3-hydroxy-1-(hydroxymethyl)-1-propenyl]-2-naphthalenecarbonitrile

A solution of Example 53B (3.09 g, 10 mmol), PdCl₂ (120 mg, 1 mmol),cis-2-butene-1,4-diol (1.23 mL, 15 mmol) and NaHCO₃ (1.01 g, 12 mmol) inN-methylpyrrolidinone (10 mL) was stirred at 130° C. for 1 h, cooled toroom temperature and chromatographed on silica gel with 30% ethylacetate/hexanes to provide 2.19 g of the title compound as a mixture ofdiastereomers.

MS (DCI/NH₃) m/e 269 (M+H)⁺.

EXAMPLE 62B(±)-7-Methoxy-8-(tetrahydro-3-furanyl)-2-naphthalenecarbonitrile

Example 62A (140 mg, 0.52 mmol) in methylene chloride (3 mL) at 0° C.was treated with triethylsilane (0.166 mL, 1.04 mmol) and BF₃.OEt₂(0.096 mL, 0.78 mmol), stirred at room temperature for 4 h, concentratedand chromatographed on silica gel with 25% ethyl acetate/hexanes toprovide 100 mg of the title compound.

MS (DCI/NH₃) m/e 271 (M+NH₄)⁺.

EXAMPLE 62C(±)-7-Methoxy-8-(tetrahydro-3-furanyl)-2-naphthalenecarboximidamidemono(methanesulfonate) salt

The title compound was prepared from Example 62B (96 mg, 0.379 mmol) andthe procedure from Example 55D.

¹H NMR (300 MHz, DMSO-d₆) δ 2.20 (m, 1H), 2.33 (m, 1H), 2.39 (s, 3H),3.99 (s, 3H), 3.90-4.03 (m, 3H), 4.11 (m, 1H), 4.42 (m, 1H), 7.64 (d,1H), 7.68 (d, 1H), 8.01 (d, 1H), 8.10 (d, 1H), 8.70 (s, 1H), 9.01 (br s,2H), 9.41 (br s, 2H), MS (DCI/NH₃) m/e 271 (M+H)⁺. Anal. calcd forC₁₆H₁₈N₂O₂.1.2CH₃SO₃H: C, 53.57; H, 5.96; N, 7.26. Found: C, 53.67; H,5.78; N, 6.72.

EXAMPLE 636-[[4-(2-Aminoethyl)phenyl]ethynyl]-2-naphthalenecarboximidamidemono(trifluoroacetate) salt EXAMPLE 63A6-(Trimethylsilylethynyl)-2-naphthalenecarbonitrile

Example 28B and trimethylsilylacetylene were submitted to the conditionsdescribed in Example 42C to provide the title compound.

MS (DCI/NH₃) m/e 267 (M+NH₄)⁺.

EXAMPLE 63B 6-Ethenyl-2-naphthalenecarbonitrile

A mixture of Example 63A (0.4 g, 1.6 mmole) and K₂CO₃ (0.4 g, 3.2 mmole)in methanol (16 mL) was stirred at room temperature for 18 h,concentrated, treated with water and extracted with methylene chloride.The organic layer was washed with 0.5 NHCl and brine, dried (MgSO₄) andevaporated to provide the title compound.

MS (DCI/NH₃) m/e 195 (M+NH₄)⁺.

EXAMPLE 63C 4-Bromo-(N-tert-butoxycarbonyl)phenethylamine

4-Bromophenethylamine and di-t-butyldicarbonate were subjected to theconditions described in Synthesis, 48, 1986 to provide the titlecompound.

MS (DCI/NH₃) m/e 319 (M+NH₄)⁺.

EXAMPLE 63D6-[[4-(2-N-tert-butoxycarbonylaminoethyl)phenyl]ethynyl]-2-naphthalenecarbonitrile

The title compound was obtained with Examples 63B and C from theprocedure described in Example 57B to provide the title compound.

MS (DCI/NH₃) m/e 414 (M+NH₄)⁺.

EXAMPLE 63E6-[[4-(2-Aminoethyl)phenyl]ethynyl]-2-naphthalenecarboximidamidemono(trifluoroacetate) salt

The title compound was prepared with Example 63D and the procedure ofExample 5B.

¹H NMR (300 MHz, DMSO-d₆) δ 2.90 (t, 2H), 3.09 (m, 2H) 7.36 (d, 2H),7.60 (d, 2H), 7.76 (d, 2H), 7.76 (dd, 1H), 7.85 (s, 2H), 7.87 (dd, 1H),8.13 (d, 1H), 8.18 (d, 1H), 8.31 (s, 1H), 8.50 (s, 1H), 9.18 (s, 2H),9.45 (s, 2H); MS (DCI/NH₃) m/e 314 (M+H)⁺. Anal. calcd forC₂₁H₁₉N₃.2TFA.H₂O: C, 53.67; H, 4.14; N, 7.15. Found: C, 53.37; H, 3.93;N, 7.17.

EXAMPLE 64 7-Methoxy-8-[2-pyrimidinyl(oxy)]-2-naphthalenecarboximidamidemono(trifluoroacetate) EXAMPLE 64A7-Methoxy-8-[2-pyrimidinyl(oxy)]-2-naphthalenecarbonitrile

Example 4A (125 mg, 0.627 mmol) and 2-chloropyrimidine (143 mg, 1.25mmol) were subjected to the procedure described in Example 6A to provide101 mg of the title compound.

MS (DCI/NH₃) m/e 278 (M+H)⁺.

EXAMPLE 64B7-Methoxy-8-[2-pyrimidinyl(oxy)]-2-naphthalenecarboximidamidemono(trifluoroacetate)

The title compound was prepared with Example 64A and the procedure ofExample 1B.

¹H NMR (300 MHz, DMSO-d₆) δ 2.51 (s, 3H), 3.83 (s, 3H), 7.18 (t, 1H),7.70 (dd, 1H), 7.80 (d, 1H), 8.05 (d, 1H), 8.19 (d, 1H), 8.34 (s, 1H),8.62 (d, 2H), 9.07 (br s, 2H), 9.45 (br s, 2H); MS (DCI/NH₃) m/e 295(M+H)⁺. Anal. calcd for C₂₀H₁₆N₄O₄.1.33TFA: C, 40.48; H, 2.60; N, 8.35.Found: C, 40.25; H, 2.94; N, 8.92.

EXAMPLE 65 7-Methoxy-8-[2-thiazoyl(oxy)]naphthalene-2-carboximidamidemono(trifluoroacetate) salt EXAMPLE 65A

A mixture of Example 4A (250 mg, 1.25 mmol), 2-bromothiazole (225 mL,2.50 mmol) and CsF (209 mg, 1.38 mmol) in DMSO (4 mL) was stirred at120° C. for 4 days, cooled and chromatographed on silica gel with 30%ethyl acetate/hexanes to provide 162 mg of the title compound.

MS (DCI/NH₃) m/e 283 (M+H)⁺.

EXAMPLE 65B 7-Methoxy-8-[2-thiazoyl(oxy)]naphthalene-2-carboximidamidemono(trifluoroacetate) salt

The title compound was prepared with Example 65A and the procedure ofExample 1B.

¹H NMR (300 MHz, DMSO-d₆) δ 3.98 (s, 3H) 7.25 (m, 2H), 7.73 (dd, 1H),7.86 (d, 1H), 8.12 (d, 1H), 8.22 (d, 1H), 8.35 9.09 (bs, 2H), (s, 1H),9.48 (bs, 2H). MS (DCI/NH₃) m/e 300 (M+H)⁺. Anal. calcd forC₁₅H₁₃N₃O₂S.TFA: C, 49.40; H, 3.41; N, 10.70. Found: C, 49.10; H, 3.40;N, 10.69.

EXAMPLE 66 7-Methoxy-8-(4-nitrophenoxy)-2-naphthalenecarboximidamidemono(trifluoroacetate) salt EXAMPLE 66A7-Methoxy-8-(4-nitrophenoxy)-2-naphthalenecarbonitrile

The title compound was prepared from Example 4A (125 mg, 0.627 mmol),1,4-dinitrobenzene (143 mg, 1.25 mmol) and the procedure described inExample 65A to provide 227 mg of the title compound.

MS (DCI/NH₃) m/e 338 (M+NH₄)⁺.

EXAMPLE 66B 7-Methoxy-8-(4-nitrophenoxy)-2-naphthalenecarboximidamidemono(trifluoroacetate) salt

The title compound was prepared with Example 66A and the procedure ofExample 55D.

¹H NMR (300 MHz, DMSO-d₆) δ 9.43 (br s, 2H), 8.94 (br s, 2H), 8.25 (m,4H), 8.15 (d, 1H), 7.88 (d, 1H), 7.72 (dd, 1H), 7.05 (d, 2H), 3.91 (s,3H), 2.30 (s, 3H); MS (DCI/NH₃) m/e 338 (M+H)⁺. Anal. calcd forC₁₈H₁₅N₃O₄.1.75CH₃SO₃H: C, 46.93; H, 4.39; N, 8.31. Found: C, 47.17; H,4.32; N, 8.12.

EXAMPLE 67 7-Methoxy-8-pentafluorophenoxy-2-napthalenecarboximidamidemono(trifluoroacetate) salt EXAMPLE 67A7-Methoxy-8-pentafluorophenoxy-2-naphthalenecarbonitrile

Example 4A (100 mg, 0.50 mmol) and hexafluorobenzene (115 mL, 1.00 mmol)were subjected to the procedure described in Example 65A to provide 150mg of the title compound.

MS (DCI/NH₃) m/e 383 (M+NH₄)⁺.

EXAMPLE 67B 7-Methoxy-8-pentafluorophenoxy-2-naphthalenecarboximidamidemono(trifluoroacetate) salt

The title compound was prepared with Example 67A and the procedure ofExample 55D.

¹H NMR (300 MHz, DMSO-d₆) δ 2.31 (s, 3H), 3.82 (s, 3H), 7.87 (dd, 1H),7.88 (d, 1H), 8.02 (d, 1H), 8.20 (d, 1H), 8.65 (s, 1H), 9.04 (br s, 2H),9.47 (br s, 2H); MS (DCI/NH₃) m/e 383 (M+H)⁺. Anal. calcd forC₁₈H₁₁N₂F₅O₂.1.2CH₃SO₃H: C, 46.67; H, 3.19; N, 5.68. Found: C, 46.55; H,3.00; N, 5.58.

EXAMPLE 68 7-Methoxy-8-[N-2-phenyl(amino)]-2-naphthalenecarboximidamidemono(trifluoroacetate) salt EXAMPLE 68A7-Methoxy-8-[N-2-phenyl(amino)]-2-naphthalenecarbonitrile

A solution of Example 25A (309 mg, 1.00 mmol), aniline (0.109 mL, 1.2mmol), NaO^(t)Bu (115 mg, 1.2 mmol), Pd₂(dba)₃ (10 mg, 0.01 mmol) anddppf (17 mg, 0.03 mmol) in toluene (5 mL) was stirred for 3 h at 100°C., cooled and chromatographed on silica gel with 10% ethylacetate/hexanes to provide 175 mg of the title compound.

MS (DCI/NH₃) m/e 275 (M+H)⁺.

EXAMPLE 68B 7-Methoxy-8-(N-2-phenylamino)-2-naphthalenecarboximidamidemono(trifluoroacetate) salt

The title compound was prepared with Example 68A and the procedure ofExample 55D.

¹H NMR (300 MHz, DMSO-d₆) δ 3.95 (s, 3H), 5.92 (bs, 1H), 6.61 (d, 2H),6.94 (t, 1H), 7.16 (dd, 2H), 7.45 (dd, 1H), 7.48 (d, 1H), 7.76 (d, 1H),7.88 (d, 1H), 8.13 (d, 1H), 9.08 (bs, 2H), 9.31 (bs, 2H). MS (DCI/NH₃)m/e 292 (M+H)⁺. Anal. Calcd for C₁₈H₁₇N₃O.TFA: C, 59.26; H, 4.48; N,10.37. Found: C, 59.20; H, 4.32; N, 10.15.

EXAMPLE 69 N-(6-Aminoiminomethyl-2-naphthalenyl)-N′-benzylureamono(trifluoroacetate) salt EXAMPLE 69AN-(6-Cyano-2-naphthalenyl)-N′-benzylurea

The title compound was prepared with Example 40A, benzylamine and theprocedure from Example 40B.

MS (DCI/NH₃) m/e 302 (M+H)⁺.

EXAMPLE 69B N-(6-Aminoiminomethyl-2-naphthalenyl)-N′-benzylureamono(trifluoroacetate) salt

The title compound was prepared with Example 69A and the procedure fromExample 40D.

¹H NMR (300 MHz, DMSO-d₆) δ 4.35 (d, 2H), 6.91 (t, 1H), 7.35-7.24 (m,5H), 7.59 (dd, 1H), 7.72 (dd, 1H), 7.95 (d, 1H), 7.96 (d, 1H), 8.22 (d,1H), 8.35 (d, 1H), 8.92 (br s, 2H), 9.13 (s, 1H), 9.32 (br s, 2H). MS(DCI/NH₃) m/e 319 (M+H)⁺. Anal. calcd for C₁₉H₁₈N₄O.TFA: C, 50.57; H,4.24; N, 15.72. Found: C, 50.34; H, 4.15; N, 15.54.

EXAMPLE 70 N-(6-Aminoiminomethyl-2-naphthalenyl)-N′-methylureamono(trifluoroacetate) salt EXAMPLE 70AN-(6-Cyano-2-naphthalenyl)-N′-methylurea

The title compound was prepared with Example 40A (221.2 mg, 1.00 mmole)and methylamine (2.3 mL, 2.34 mmol) in THF (10 mL) according to theprocedure from Example 40B.

MS (DCI/NH₃) m/e 226 (M+H)⁺.

EXAMPLE 70B N-(6-Aminoiminomethyl-2-naphthalenyl)-N′-methylureamono(trifluoroacetate) salt

The title compound was prepared with Example 70A and the procedure ofExample 40D.

¹H NMR (300 MHz, DMSO-d₆) δ 2.69 (d, 3H), 6.32 (q, 1H), 7.60 (dd, 1H),7.73 (dd, 1H), 7.93 (d, 1H), 7.95 (d, 1H, 8.19 (d, 1H), 8.49 (d, 1H),9.09 (s, 1H), 9.15 (br. s, 4H); MS (DCI/NH₃) m/e 243 (M+H)⁺. Anal. calcdfor C₁₃H₁₄N₄O.TFA: C, 50.57; H, 4.24; N, 15.72. Found: C, 50.34; H,4.15; N, 15.54.

EXAMPLE 71 N-(6-Aminoiminomethyl-2-naphthalenyl)-N′-isopropylureamono(trifluoroacetate) salt EXAMPLE 71AN-(6-Cyano-2-naphthalenyl)-N′-isopropylurea

The title compound was prepared with Example 40A, isopropylamine and theprocedure from Example 40B.

MS (DCI/NH₃) m/e 254 (M+H)⁺.

EXAMPLE 71B N-(6-Aminoiminomethyl-2-naphthalenyl)-N′-isopropylureamono(trifluoroacetate) salt

The title compound was prepared with Example 71A and the procedure ofExample 5B.

¹H NMR (300 MHz, DMSO-d₆) δ 1.13 (d, 6H), 3.76-3.84 (m, 1H), 6.28 (d,1H), 7.55 (dd, 1H), 7.72 (dd, 1H), 7.94 (d, 1H), 7.95 (d, 1H), 8.19 (d,1H), 8.34 (d, 1H), 8.85 (s, 1H), 9.3 (br s, 2H), 9.0 (br s, 2H); MS(DCI/NH₃) m/e 271 (M+H)⁺. Anal. calcd for C₁₅H₁₈N₄O.TFA: C, 53.12; H,4.98; N, 14.58. Found: C, 15.13; H, 4.84; N, 14.50.

EXAMPLE 72 N-(6-Aminoiminomethyl-2-naphthalenyl)-N′-phenyl-N′-methylureamono(trifluoroacetate) salt EXAMPLE 72AN-(6-Cyano-2-naphthalenyl)-N′-phenyl-N′-methylurea

The title compound was prepared with Example 40A, N-methyl-N-phenylamineand the procedure from Example 40B.

MS (DCI/NH₃) m/e 302 (M+H)⁺.

EXAMPLE 72BN-(6-Aminoiminomethyl-2-naphthalenyl)-N′-phenyl-N′-methylureamono(trifluoroacetate) salt

The title compound was prepared with Example 72A and the procedure ofExample 40D.

¹H NMR (300 MHz, DMSO-d₆) δ 3.33 (s, 3H), 7.25-7.47 (m, 5H), 7.71-7.77(m, 2H), 7.95 (two overlaping doublets, 2H), 8.16 (d, 1H), 8.35 (d, 1H),8.64 (s, 1H), 8.96 (br s, 2H), 9.34 (br s, 2H); MS (DCI/NH₃) m/e 319(M+H)⁺. Anal. calcd for C₂₀H₁₇N₄O.TFA: C, 58.33; H, 4.43; N, 11.96.Found: C, 58.38; H, 4.69; N, 11.82.

EXAMPLE 73 6-Aminonaphthalene-2-carboximidamide mono (trifluoroacetate)salt EXAMPLE 73A 6-Phenylcarbomoyl-2-naphthalenecarbonitrile

The title compound was prepared from Example 40A, phenol and theprocedure from Example 40B.

MS (DCI/NH₃) m/e 289 (M+H)⁺.

EXAMPLE 73B 6-Aminonaphthalene-2-carboximidaamide mono(trifluoroacetate)salt

The title compound was prepared from Example 73A and the procedure ofExample 40D.

¹H NMR (300 MHz, DMSO-d₆) δ 6.01 (br s, 2H), 6.86 (d, 1H), 7.06 (dd,1H), 7.58-7.67 (m, 2H), 7.74 (d, 1H), 8.21 (d, 1H), 8.74 (br s, 2H),9.16 (br s, 2H); MS (DCI/NH₃) m/e 196 (M+H)⁺. Anal. calcd forC₁₂H₁₀N₃.TFA: C, 52.18; H, 4.04; N, 14.04. Found: C, 51.92; H, 3.87; N,13.80.

EXAMPLE 74 N-(6-aminoiminomethyl-2-naphthalenyl)-N′-cyclohexylureamono(trifluoroacetate) salt EXAMPLE 74AN-(6-Cyano-2-naphthalenyl)-N′-cyclohexylurea

The title compound was piepaiedwitlh Example 40A, cyclohexylamine andthe procedure from Example 40B.

MS (DCI/NH₃) m/e 294 (M+H)⁺.

EXAMPLE 74B N-(6-aminoiminomethyl-2-napthalenyl)-N′-cyclohexylureamono(trifluoroacetate) salt

The title compound was prepared with Example 74A and the procedure ofExample 40D.

¹H NMR (300 MHz, DMSO-d₆) δ 1.14-1.39 (m, 5H), 1.54-1.58 (m, 1H),1.65-1.72 (m, 2H), 1.81-1.86 (m, 2H), 3.46-3.52 (m, 1H), 6.36 (d, 1H),7.55 (dd, 1H), 7.72 (dd, 1H), 7.93 (d, 1H), 7.95 (d, 1H), 8.18 (d, 1H),8.35 (d, 1H), 8.87 (s, 1H), 9.00 (br s, 2H), 9.28 (br s, 2H); MS(DCI/NH₃) m/e 311 (M+H)⁺. Anal. calcd for C₁₉H₂₁N₄O.TFA: C, 56.60; H,5.46; N, 13.20. Found: C, 56.61; H, 5.72; N, 13.03.

EXAMPLE 75 N-(6-aminoiminomethyl-2-naphthalenyl)-N′-benzyloxyureamono(trifluoroacetate) salt EXAMPLE 75AN-(6-cyano-2-naphthalenyl)-N′-benzyloxyurea

The title compound was prepared with Example 40A, O-benzylhydroxylamineand the procedure from Example 40B.

MS (DCI/NH₃) m/e 318 (M+H)⁺.

EXAMPLE 75B N-(6-aminoiminomethyl-2-naphthalenyl)-N′-benzyloxyureamono(trifluoroacetate) salt

The title compounud was prepared with Example 75A and the procedure ofExample 40D.

¹H NMR (300 MHz, DMSO-d₆) δ 4.87 (s, 2H), 7.25-7.42 (m, 3H), 7.48-7.51(m, 2H), 7.75 (dd, 1H), 7.75 (dd, 1H), 7.97 (d, 2H), 8.301 (d, 1H), 8.38(d, 1H), 8.97 (br s, 2H), 9.21 (s, 1H), 9.35 (br s, 2H), 9.77 (s, 1H);MS (DCI/NH₃) m/e 335 (M+H)⁺. Anal. calcd for C₁₉H₁₈N₄O₂.TFA: C, 56.25;H, 4.27; N, 12.49. Found: C, 56.26; H, 4.39; N, 12.30.

EXAMPLE 76 1,1-Dimethylethyl[4-[[(6-aminoiminomethyl-2-naphthalenyl)amino]carbonyl]phenyl]carbamatemono(trifluoroacetate) salt EXAMPLE 76A6-Amino-2-naphthalenecarbonitrile

Sulfuric acid (45 mL) was treated with Example 40B (6.5 g), stirred for30 min, warmed to room temperature for 20 min, poured onto ice, dilutedwith water to approximately 500 mL, cooled to 0° C. and treated with 50%aq sodium hydroxide such that the temperature did not exceed 35° C. Thelight solid which precipitated was filtered, washed with water to pH 7,dried under vacuum and purified on silica gel with 20% ethylacetate/hexanes to provide 3.3 g of the title compound. MS (DCI/NH₃) m/e169 (M+H)⁺.

EXAMPLE 76B 1,1-Dimethylethyl[4-[[(6-cyano-2-naphthalenyl)amino]carbonyl]phenyl]carbamatemono(trifluoroacetate) salt

The title compound was prepared from Example 76A,4-N-Boc-aminoethylbenzoic acid, the procedure from Example 35B withmethylene chloride in place of THF.

MS (DCI/NH₃) m/e 417 (M+H)⁺.

EXAMPLE 76C 1,1-Dimethylethyl[4-[[(6-aminoiminomethyl-2-naphthalenyl)amino]carbonyl]phenyl]carbamatemono(trifluoroacetate) salt

The title compound was prepared with Example 76B and the procedure ofExample 40D.

¹H NMR (300 MHz, DMSO-d₆) δ 3.30 (s, 9H), 4.22 (d, 2H), 7.42 (d, 2H),7.49 (t, 1H), 7.79 (dd, 1H), 7.95-8.00 (m, 3H), 8.09 (d, 2H), 8.42 (s,1H), 8.63 (d, 1H), 9.18 (br s, 4H), 10.58 (s, 1H); MS m/e 434 (M+H)⁺.Anal. calcd for C₂₄H₂₇N₅O₃.TFA: C, 59.56; H, 5.00; N, 10.29. Found: C,58.55; H, 4.84; N, 10.41.

EXAMPLE 77N-[6-(Aminoiminomethyl)-2-naphthalenyl]-4-(aminomethyl)benzamidemono(trifluoroacetate) salt EXAMPLE 77AN-[6-(Aminoiminomethyl)-2-naphthalenyl]-4-(aminomethyl)benzamidemono(trifluoroacetate) salt

A solution of Example 76B (35 mg, 0.07 mmole) in 1:1 TFA/methylenechloride was stirred at room temperature for 1 h then concentrated. Theresidue was dissolved in water (12 mL), filtered through a 0.45 μ filterand concentrated. The solid was suspended in diethyl ether and filteredto yield 27 mg of the title compound as a white solid.

¹H NMR (300 MHz, DMSO-d₆) δ 4.17 (q, 2H), 7.65 (d, 2H), 7.80 (dd, 1H),7.99 (dd, 1H), 8.06-8.12 (m, 4H), 8.30 (br s, 2H), 8.44 (d, 1H), 8.64(d, 1H), 9.13 (br s, 2H), 9.40 (br s, 2H), 10.70 (s, 1H); MS (DCI/NH₃)m/e 319 (M+H)⁺. Anal. calcd for C₁₉H₁₈N₄O.2.25TFA.0.5H₂O: C, 48.34; H,3.67; N, 9.59. Found: C, 48.45; H, 3.74; N, 9.45.

EXAMPLE 78 Ethyl [6-(aminoiminomethyl)-2-naphthalenyl]carbamatemono(trifluoroacetate) salt EXAMPLE 78A Ethyl(6-cyano-2-naphthalenyl)carbamate mono(trifluoroacetate) salt

The title compound was prepared with Example 40A, ethanol and theprocedure from Example 40B.

MS (DCI/NH₃) m/e 241 (M+H)⁺.

EXAMPLE 78B Ethyl [6-(aminoiminomethyl)-2-naphthalenyl]carbamatemono(trifluoroacetate) salt

The title compound was prepared with Example 78A and the procedure ofExample 40D.

¹H NMR (300 MHz, DMSO-d₆) δ 1.29 (t, 3H), 4.19 (q, 2H), 7.69 (dd, 1H),7.76 (dd, 1H), 8.1 (d, 2H), 8.23 (d, 1H), 8.38 (d, 1H), 9.03 (br s, 2H),9.33 (br s, 2H), 10.11 (s, 1H); MS (DCI/NH₃) m/e 258 (M+H)⁺. Anal. calcdfor C₁₄H₁₅N₃O₂.TFA: C, 51.76; H. 4.34; N, 11.32. Found: C, 51.32; H,4.15; N, 10.93.

EXAMPLE 79 1,1-dimethylethyl[4-[[[6-(aminoiminomethyl)-2-naphthalenyl)amino]carbonyl]amino]phenyl]carbamatemono(trifluoroacetate) salt EXAMPLE 79A 1,1-Dimethyl[4-[[[(6-cyano-2-naphthalenyl)amnino]carbonyl]amino]phenyl]carbamate

The title compound was prepared with Example 40B,4-(N-tert-butoxycarbonylamino)-aminobenzene and the procedure fromExample 40C.

MS (DCI/NH₃) m/e 403 (M+H)⁺.

EXAMPLE 79B 1,1-dimethylethyl[4-[[[6-aminoiminomethyl)-2-naphthalenyl)amino]carbonyl]amino]pheny]carbamatemono(trifluoroacetate) salt

The title compound was prepared with Example 79A and the procedure ofExample 40D.

¹H NMR (300 MHz, DMSO-d₆) δ 1.22 (s, 9H), 7.38 (s, 4H), 7.62 (dd, 1H),7.75 (dd, 1H), 8.00 (d, 2H), 8.27 (d, 1H), 8.38 (d, 1H), 8.77 (s, 1H),8.90 (br s, 2H), 9.16 (s, 1H), 9.20 (s, 1H), 9.33 (br s, 2H); MS(DCI/NH₃) m/e 420 (M+H)⁺. Anal. calcd for C₂₃H₂₅N₅O₃.2TFA: C, 56.28; H,4.91; N, 13.13; Found: C, 56.18; H, 5.07; N, 12.44.

EXAMPLE 80 (E)-6-[2-(Phenylthio)ethenyl]-2-naphthalenecarboximidamidemono(trifluoroacetate) salt EXAMPLE 80A(E)-6-[2-(Phenylthio)ethenyl]-2-naphthalenecarbonitrile

The title compound was prepared from Example 55B, phenylvinyl sulfideand the procedure of Example 57B.

MS (DCI/NH₃) m/e 305 (M+NH₄)⁺.

EXAMPLE 80B (E)-6-[2-(Phenylthio)ethenyl]-2-naphthalenecarboximidamidemono(trifluoroacetate) salt

The title compound was prepared from Example 80A and the procedure ofExample 1B.

¹H NMR (300 MHz, DMSO-d₆) δ 6.91 (d, 1H), 7.52-7.33 (m, 5H), 7.50 (d,1H), 7.75-7.83 (m, 1H), 7.98-8.89 (m, 1H), 8.08-8.80 (m, 3H), 8.44 (m,1H), 9.03 (s, 2H), 9.40 (s, 2H); MS (DCI/NH₃) m/e 305 (M+H)⁺. Anal.calcd for C₁₉H₁₆N₂S.1.1TFA: C, 59.55; H, 4.03; N, 6.57. Found: C, 59.53;H, 4.12; N, 6.60.

EXAMPLE 81 (E)-6-[2-(2-Furanyl)ethenyl]-2-naphthalenecarboximidamidemono(trifluoroacetate) salt EXAMPLE 81A 2-Vinylfuran

A solution of methyl(triphenylphosphonium)bromide (26.78 g, 75 mmol) intoluene (80 mL) was treated with butyllithium in hexanes (27.5 mL, 68.75mmol) then furfural (6 g, 62.5 mmol), stirred for 0.5 h and distilled at69-72° C. to provide the title compound as a clear, colorless liquidwith some toluene contaminant.

MS (DCI/NH₃) m/e 83 (M+H)⁺.

EXAMPLE 81B (E)-6-[2-(2-Furanyl)ethenyl]-2-naphthalenecarbonitrile

The title compound was prepared from Examples 55B and 81A and theprocedure of Example 57B.

MS (DCI/NH₃) m/e 263 (M+NH₄)⁺.

EXAMPLE 81C (E)-6-[2-(2-Furanyl)ethenyl]-2-naphthaleneecarboximidamidemono(trifluoroacetate) salt

The title compound was prepared from Example 81B and the procedure ofExample 1B.

¹H NMR (300 MHz, DMSO-d₆) δ 6.61 (dd, 1H), 6.66 (d, 1H), 7.19 (d, 1H),7.38 (d, 1H), 7.77 (d, 1H), 7.80 (dd, 1H), 8.14-7.97 (m, 3H), 8.44 (s,1H), 9.05 (s, 2H), 9.42 (s, 2H); MS (DCI/NH₃) m/e 263 (M+H)⁺. Anal.calcd for C₁₇H₁₃N₂O.1.2TFA: C, 58.49; H, 3.85; N, 7.04. Found: C, 58.45;H, 3.78; N, 7.36.

EXAMPLE 82(E)-6-[2-(1H-Imidazol-1-yl)ethenyl]-2-naphthalenecarboximidamidemono(trifluoroacetate) salt EXAMPLE 82A(E)-6-[2-(1H-Imidazol-1-yl)etheyl]-2-naphthalenecarbonitrile

The title compound was prepared from Example 55B, 1-vinylimidazole andthe procedure of Example 42C.

MS (DCI/NH₃) m/e 263 (M+NH₄)⁺.

EXAMPLE 82B(E)-6-[2-(1H-Imidazol-1-yl)etheyl]-2-naphthalenecarboximidamidemono(trifluoroacetate) salt

The title compound was prepared from Example 82B and the procedure ofExample 40D.

¹H NMR (300 MHz, DMSO-d₆) δ 9.44 (s, 2H), 9.14 (s, 2H), 8.15 (d, 1H),8.17-8.05 (m, 4H), 7.93 (d, 1H), 7.84 (dd, 1H), 7.59 (s, 1H), 7.49 (d,1H); MS (DCI/NH₃) m/e 263 (M+H)⁺. Anal. calcd for C₁₆H₁₃N₄.2.7TFA: C,45.28; H, 2.97; N, 9.91. Found: C, 45.33; H, 3.52; N, 9.79.

EXAMPLE 83(E)-4-[2-(6-Aminoiminomethyl-2-naphthalenyl)ethenyl]benzenesulfonamidemono(trifluoroacetate) salt EXAMPLE 83A 4-vinylsulfonamide

A solution of thionyl chloride (7.5 mL) and 4-t-butylcatachol (45 mg,0.3 mmol) in DMF (9 mL) at 0° C. was treated with 4-vinylbenzenesulfonic acid sodium salt (3 g, 14.6 mmol), stirred for 6 h, stored at−10° C. for 3 days, poured into ice water and extracted with benzene.The organic layer was washed with water, dried (Na₂SO₄), filtered andconcentrated to provide 4-vilylsulfonyl chloride as a clear, colorlessoil. A portion of the chloride (1 g, 4.95 mmol) was disslolved in THF(10 mL), cooled to 0° C., treated dropwise with concentrated ammoniumhydroxide until gas evolution ceased and extracted with ethyl acetate.The combined extracts were dried (Na₂SO₄), and concentrated to provide707 mg of the title compound as a pale yellow solid.

MS (DCI/NH₃) m/e 201 (M+NH₄)⁺.

EXAMPLE 83B (E)-4-[2-(6-Cyano-2-naphthalenyl)ethenyl]benzenesulfonamide

The title compound was prepared from Example 55B, Example 83A and theprocedure of Example 57B.

MS (DCI/NH₃) m/e 352 (M+NH₄)⁺.

EXAMPLE 83C(E)-4-[2-(6-Aminoiminomethyl-2-naphthalenyl)ethenyl]benzenesulfonamidemono(trifluoroacetate) salt

The title compound was prepared from Example 83B and the procedure ofExample 40D.

¹H NMR (300 MHz, DMSO-d₆) δ 9.43 (s, 2H), 9.05 (s, 2H), 8.46 (s, 1H),8.21 (s, 1H), 8.16-7.95 (m, 3H), 7.86 (s, 2H), 7.84-7.67 (m, 2H), 7.62(d, 1H), 7.4-7.36 (m, 2H); MS (DCI/NH₃) m/e 352 (M+H)⁺. Anal. calcd forC₁₉H₁₇N₃O₂S.1.5C₂F₃O₂H: C, 50.84; H, 3.59; N, 8.11. Found: C, 50.83; H,3.89; N, 7.88.

EXAMPLE 84 (E)-4-[2-(6-Aminoiminomethyl-2-naphthalenyl)ethenyl]benzoicacid mono(trifluoroacetate) salt EXAMPLE 84A(E)-4-[2-(6-Cyano-2-naphthalenyl)ethenyl]benzoic acid

The title compound was prepared from Example 55B, 4-vinylbenzoic acidand the procedure of Example 57B.

MS (DCI/NH₃) m/e 300 (M+H)⁺.

EXAMPLE 84B (E)-4-[2-(6-Aminoiminomethyl-2-naphthalenyl)ethenyl]benzoicacid mono(trifluoroacetate) salt

The title compound was prepared with Example 84A and the procedure ofExample 40D.

¹H NMR (300 MHz, DMSO-d₆) δ 7.62-7.58 (m, 2H), 7.90 (d, 2H), 7.98 (d,1H), 8.12-8.04 (m, 3H), 8.20 (s, 1H), 8.56 (s, 1H), 9.07 (bs, 2H), 9.35(bs, 2H). MS (DCI/NH₃) m/e 317 (M+H)⁺. Anal. calcd for C₂₀H₁₆N₂O₂.TFA:C, 61.40; H, 3.98; N, 6.51. Found: C, 61.10; H, 3.63; N, 6.45.

EXAMPLE 854-[7-(Aminoiminomethyl)-2-methoxy-1-naphthalenyl]dihydro-2(3H)-furanonemono(trifluoroacetate) salt EXAMPLE 85A4-(7-Cyano-2-methoxy-1-naphthalenyl)dihydro-2(3H)-furanone

Example 62A (269 mg, 100 mmol) and pyridinium chlorochromate (360 mg,1.67 mmol) in methylene chloride (15 mL) were stirred at roomtemperature for 24 h, filtered through Celite® and concentrated. Theresidue was chrormatographed on silica gel with 20% ethylacetate/hexanes to provide 170 mg of the title compound.

MS (DCI/NH₃) m/e 285 (M+NH₄)⁺.

EXAMPLE 85B4-[7-(Aminoiminomethyl)-2-methoxy-1-naphthalenyl]dihydro-2(3H)-furanonemono(trifluoroacetate) salt

The title compound was prepared from Example 85A and the procedure ofExample 40D.

¹H NMR (300 MHz, DMSO-d₆) δ 2.96-2.75 (m, 2H), 3.96 (s, 3H), 4.33 (m,1H), 4.66 (t, 1H), 8.85 (m, 1H), 7.68 (dd, 1H), 7.73 (d, 1H), 8.08 (d,1H), 8.12 (d, 1H), 8.67 (s, 1H), 9.14 (s, 2H), 9.43 (s, 2H); MS(DCI/NH₃) m/e 285 (M+H)⁺. Anal. calcd for C₁₆H₁₆N₂O₃.1.1TFA: C, 53.72;H, 4.24; N, 6.91. Found: C, 53.75; H, 4.26; N, 6.94.

EXAMPLE 867-Methoxy-8-(1-acetyl-1H-pyrazolyl)-2-naphthalenecarboximidamidemono(trifluoroacetate) salt EXAMPLE 86A7-Methoxy-8-(1-acetyl-1H-pyrazolyl)-2-naphthalenecarbonitrile

A solution of Example 53F (90 mg, 0.361 mmol) in THF (2 mL) was treatedwith a 0.5 M solution of potassium bis(trimethylsilyl)amide in toluene(0.866 mL, 0.433 mmol), stirred for 5 min, treated with acetyl chloride(38 mL, 0.542 mmol), stirred for 10 min and concentrated. The crudeproduct was chromatographed on silica gel with 25% ethyl acetate/hexanesto yield 67 mg of the title compound.

MS MS (DCI/NH₃) m/e 309 (M+NH₄)⁺.

EXAMPLE 86B7-Methoxy-8-(1-acetyl-1H-pyrazolyl)-2-naphthalenecarboximidamidemono(trifluoroacetate) salt

The title compound was prepared with Example 86A and the procedure ofExample 40D.

¹H NMR (300 MHz, DMSO-d₆) δ 3.89 (s, 3H), 7.59 (d, 1H), 7.92 (s, 2H),8.06 (d, 1H), 8.12 (d, 1H), 8.28 (s, 1H), 8.94 (s, 2H), 9.34 (s, 2H); MS(DCI/NH₃) m/e 309 (M+H)⁺. Anal. calcd for C₁₇H₁₆N₄O₂.1.9TFA: C, 47.59;H, 3.44; N, 10.67. Found: C, 54.03; H, 4.06; N, 13.26.

EXAMPLE 877-Methoxy-8-[1-(methylsulfonyl)-1H-4-pyrazolyl]-2-naphthalenecarboximidamidemono(trifluoroacetate) salt EXAMPLE 87A7-Methoxy-8-[1-(methylsulfonyl)-1H-4-pyrazolyl]-2-naphthalenecarbonitrile

The title compound was prepared from Example 53F (190 mg, 0.762 mmol),methanesulfonyl chloride (0.088 mL, 1.14 mmol) and the procedure ofExample 86A to provide 122 mg of the title compound.

MS (DCI/NH₃) m/e 345 (M+NH₄)⁺.

EXAMPLE 87B7-Methoxy-8-[1-(methylsulfonyl)-1H-4-pyrazolyl]-2-naphthalenecarboximidamidemono(trifluoroacetate) salt

The title compound was prepared from Example 87A and the procedure ofExample 40D.

¹H NMR (300 MHz, DMSO-d₆) δ 2.75 (s, 3H), 3.98 (s, 3H) 7.64 (dd, 1H),7.78 (d, 1H), 8.15 (s, 1H), 8.18 (s, 1H), 8.21 (s, 1H), 8.24 (s, 1H),8.62 (s, 1H), 8.97 (s, 2H), 9.40 (s, 2H); MS (DCI/NH₃) m/e 345 (M+H)⁺.Anal. calcd for C₁₆H₁₆N₄O₃S.1.4TFA: C, 44.75; H, 3.47; N, 11.09. Found:C, 44.59; H, 3.86; N, 11.38.

EXAMPLE 88 (E)-4-[2-(6-Aminoiminomethyl-2-naphthalenyl)ethenyl]benzamidemono(trifluoroacetate) salt EXAMPLE 88A(E)-4-[2-(6-Cyano-2-naphthalenyl)ethenyl]benzamide

Example 85A (160 mg, 0.54 mmol) in thionyl chloride (4 ml) was refluxedfor 0.5 h, cooled to 0° C., treated with concentrated aqueous ammoniauntil gas evolution ceased, diluted with ethyl acetate, heated todissolve residual solids, washed with water, dried (MgSO₄) andconcentrated to provide 100 mg of the title compound as an orange solid.

MS (DCI/NH₃) m/e 316 (M+NH₄)⁺.

EXAMPLE 88B(E)-4-[2-(6-Aminoiminomethyl-2-naphthalenyl)ethenyl]benzamidemono(trifluoroacetate) salt

The title compound was prepared with Example 88A and the procedure ofExample 1B.

¹H NMR (300 MHz, DMSO-d₆) δ 7.34 (hr, 1H), 7.51 (d, 1H), 7.56 (d, 2H),7.73 (d, 2H), 7.82 (m, 2H), 7.90 (d, 2H), 7.96 (br, 1H), 8.09 (q, 3H),8.17 (s, 1H), 8.43 (s, 1H), 9.01 (s, 2H), 9.40 (s, 2H); MS (DCI/NH₃) m/e316 (M+H)⁺. Anal. calcd for C₂₀H₁₇N₃O.1.1TFA: C, 60.09; H 4.11; N, 9.44.Found: C, 60.22; H, 4.13; N, 8.79.

EXAMPLE 89 6-[2-(4-Aminophenyl)ethoxy]-2-naphthalenecarboximidamidemono(trifluoroacetate) salt EXAMPLE 89A6-[2-(4-Aminophenyl)ethoxy]-2-naphthalenecarbonitrile

A solution of Example 4A, (300 mg), Cs₂CO₃ (1.2 g ),4-aminophenethylbromide (470 mg) and tetrabutylammonium iodide (10 mg)in DMF (5 ml) was stirred for 18 h at room temperature, diluted withwater and extracted with ethyl acetate. The organic extract was washedwith saturated aq NaHCO₃ and brine, dried (Na₂SO₄) and concentrated toprovide 200 mg of the title compound as a dark brown oil.

MS (DCI/NH₃) m/e 306 (M+NH₄)⁺.

EXAMPLE 89B 6-[2-(4-Aminophenyl)ethoxy]-2-naphthalenecarboximidamidemono(trifluoroacetate) salt

The title compound was prepared with Example 89A according to theprocedure of Example 5B.

¹H NMR (300 MHz, DMSO-d₆) δ 3.15 (t, 2H), 3.6 (bs, 3H), 4.35 (t, 2H),6.93 (d, 2H), 7.24 (d, 2H) 7.38 (dd, 1H), 7.55 (d, 1H), 7.78 (dd, 1H),7.98 (dd, 1H), 8.21 (d, 1H), 8.4 (d, 1H), 9.21 (bs, 2H), 9.39 (bs, 2H);MS m/e 306 (M+H)⁺. Anal. calcd for C₁₉H₁₉N₃O.2TFA: C, 51.79; H, 3.97; N,7.88; Found: C, 50.99; H, 4.68; N, 7.59.

EXAMPLE 90 Methyl[3-methoxy-6-(aminoiminomethyl)-4-naphthalenyl]carbamatemono(trifluoroacetate) salt EXAMPLE 90A7-Methoxy-2-trifluoromethanesulfonyloxy naphthalene

A solution of 7-methoxy-2-naphthol (3.24 g, 18 mmole) in DMF (20 mL) andmethylene chloride (20 mL) was treated with N-phenyltrifluoromethanesulfonimide (6.6 g, 18 mmole) and triethylamine (5.2 mL,37 mmole), stirred 20 h at room temperature, diluted with CH₂Cl₂ (100mL), washed sequentially with distilled water, 20% KOH and brine, dried(MgSO₄) and concentrated to provide the title compound as a clear oil.

MS (DCI/NH₃): m/e 272 (M +NH₄)⁺.

EXAMPLE 90B 7-Methoxy-2-naphthalenecarbonitrile

Example 90A (12 mmole), zinc cyanide (12 mmole), Pd(OAc)₂ (0.3 mmole)and triphenylphosphine (1.2 mmole) in DMF (40 mL) was heated for 6 h at85° C., diluted with ethyl acetate (200 mL), washed with saturatedNaHCO₃, brine, dried (MgSO₄) and concentrated to a dark oily residue.Purification of the residue on silica gel with 1:1 hexane:methylenechloride then CH₂Cl₂ provided 1.8 g of the title compound as a whitesolid.

MS (DCI/NH₃) m/e 201 (M +NH₄)⁺.

EXAMPLE 90C 7-Methoxy-8-nitro-2-naphthalenecarbonitrile

Example 90B (3 g, 16.4 mmole) in acetic anhydride (30 mL) at 0° C. wastreated with fuming HNO₃ (1.2 mL), and the resulting thick slurry wasdiluted with water (20 mL), stirred 20 min then filtered and dried invacuo to provide 3.69 g of the title compound as a yellow solid.

MS (DCI/NH₃) m/e 246 (M+NH₄)⁺.

EXAMPLE 90D 7-Methoxy-8-amino-2-naphthonitrile

Example 90C (3.69 g, 16.1 mmole) and 10% Pd/C (0.4 g) in ethyl acetate(100 mL) was stirred under a hydrogen atmosphere for 2 h at roomtemperature, filtered and concentrated to provide 3 g of the titlecompound as a yellow solid.

MS (DCI/NH₃) m/e 217 (M+NH₄)⁺.

EXAMPLE 90E Methyl [3-methoxy-6-cyano-4-naphthalenyl]carbamate

Example 90D (81 mg, 0.41 mmol) in dioxane (7 mL) and 10% NaOH (15 mL)was treated with methyl chloroformate (112 mg. 0.98 mmol), stirred for 2h, diluted with ethyl acetate, washed with water, dried (MgSO₄) andconcentrated to provide 105 mg of the title compound. MS (DCI/NH₃) m/e274 (M+NH₃)⁺.

EXAMPLE 90F Methyl[3-methoxy-6-(aminoiminomethyl)-4-naphthalenyl]carbamatemono(trifluoroacetate) salt

The title compound was prepared from Example 90E according to theprocedure of Example 40D. ¹H-NMR (300 MHz, DMSO-d₆) δ 9.48 (s, 2H), 8.99(s, 2H), 8.93 (br, 1H), 8.34 (s, 1H), 8.12 (d, 1H), 8.04 (d, 1H), 7.72(d, 1H), 7.65 (dd, 1H), 3.95 (s, 3H),

MS (DCI/NH₃) m/e 274 (M+H)⁺; Anal. calcd for C₁₄H₁₅N₃O₃.1.8TFA: C,44.07; H, 3.53; N, 8.74. Found: C, 44.14; H, 3.20; N, 8.53.

EXAMPLE 917-Methoxy-8-[2-pyrimidinyl(amino)[-2-naphthalenecarboximidamidebis(trifluoroacetate) salt EXAMPLE 91A7-Methoxy-8-[2-pyrimidinyl(amino)[-2-naphthalenecarbonitrile

A solution of Example 90D (230 mg, 1.2 mmole), 2-chloropyrimidine (280mg, 2 mmole), sodium-tert-butoxide (120(mg, 1.2 mmole), Pd(dba)₃CHCl₃and dppf in toluene (5 mL) was heated in a sealed tube for 18 h at 100°C., diluted with ethyl acetate (100 mL), washed with brine, dried(MgSO₄) and concentrated to provide 100 mg of a brown oil.

MS (DCI/NH₃) m/e 294 (M+NH₄)⁺.

EXAMPLE 91B7-Methoxy-8-[2-pyrimidinyl(amino)]-2-naphthalenecarboximidamidebis(trifluoroacetate) salt

The title compound was prepared in a manner analogous to that of Example40D. ¹H-NMR (300 MHz, DMSO-d₆) δ 9.43 (s, 2H), 9.11 (s, 2H), 8.46 (s,1H), 8.16 (br, 3H), 8.15 (d, 1H), 8.04 (d, 1H), 7.82 (dd, 1H), 7.75 (d,1H), 7.54 (s, 1H) 7.50 (d, 1H), 4.08 (d, 2H); MS (DCI/NH₃) m/e 294(M+H)⁺. Anal. calcd for C₁₆H₁₅N₅O.3.8TFA: C, 39.01; H, 2.61; N, 9.64;Found: C, 39.01; H, 3.06; N, 9.63.

EXAMPLE 926-(aminoiminomethyl)-N-[4-(hydroxymethyl)phenyl]-2-naphthalenecarboxamide,mono(trifluoroacetate)(salt) EXAMPLE 92A4-amino-benzyloxy-tert-butyldimiethylsilyl ether

A solution of 4-aminobenzyl alcohol (1 g, 8.1 mmol) in DMF (20 mL) wastreated with imidazole (0.54 g, 8.1 mmol) and tert-butyl dimethylsilylchloride (1.22 g, 8.12 mmol), stirred overnight at room temperature,diluted with ethyl acetate (100 mL), washed with 1 N H₃PO₄, saturatedNaHCO₃ and 10% NaCl, dried (Na₂SO₄) and concentrated to an oil which waspurified on silica gel with 3:1 hexanes: ethyl acetate to provide 0.5 gof a clear oil.

MS m/z 238 (M+H)⁺.

EXAMPLE 92B

Example 92A (0.3, 1.1 mmol) and 6-carboxy-2-naphthonitrile, Example 8E(0.2 g, 1 mmol) were processed as described in Example 95C to provide100 mg of the desired compound.

MS m/z 434 (M+NH₄)⁺.

EXAMPLE 92C

A solution of Example 92B in 1 M tetrabutyl ammonium fluoride THFsolution (2 mL) was stirred for 1 hour at room temperature, quenchedwith 10% NH₄Cl solution (50 mL) and diluted with ethyl acetate (100 mL).The layers were separated, and the organic layer was washed with 10%NaCl, dried (MgSO₄) and concentrated to provide a light brown oil whichwas triturated with methylene chloride and filtered to provide 0.1 g ofthe desired compound as a white solid.

MS m/z 320 (M+NH₄)⁺.

EXAMPLE 92D6-(aminoiminomethyl)-N-[4-(hydroxymethyl)phenyl]-2-naphthalenecarboxamide,mono(trifluoroacetate)(salt)

Example 92C (0.1 g, 0.33 mmol) was processed and purified according tothe procedure in Example 95D to provide 15 mg of the desired compound.

MS m/z 320 (M+H)⁺; ¹H NMR 300 MHz, (DMSO-d₆): δ 10.45 (s, 1H), 9.45 (bs,4H), 8.75 (s, 1H), 8.59 (s, 1H), 8.32 (d, 1H), 8.22 (d, 1H), 8.18 (dd,1H), 7.92 (dd, 1H), 7.85 (d, 2H), 7.45 (d, 2H), 4.20 (s, 2H); Anal.calc'd for C₁₉H₁₇N₃O₂.TFA: C, 58.20; H, 4.19; N, 9.70. Found: C, 57.80;H, 3.91; N, 9.35.

EXAMPLE 93 6-(4-aminophenyl)-2-naphthalenecarboximidamide,bis(trifluoroacetate) salt EXAMPLE 93A

6-cyano-2-naphthalene boronic acid (0.3 g, 1.64 mmol), 4-iodoaniline(0.36 g, 1.64 mmol), Palladium[1,1′-Bis(diphenylphosphino)-ferrocene]dichloride (0.13 g, 0.164 mmol) and CsF (0.75 g, 4.92 mmol) are mixedtogether in DMF (8 mL) heated 20 hours. at 80° C. The mixture is dilutedwith ethyl acetate (100 mL) washed with 1 N H₃PO₄, saturated NaHCO₃, 10%NaCl, dried over anhydrous sodium sulfate. The drying agent filtered,solvent removed under vacuum leaving a brown solid. The solid ispurified on silica gel eluting with 3:1 hexanes: ethyl acetate. Thefractions corresponding to the desired compound are concentrated undervacuum leaving a yellow solid. 0.2 g, 75%.

MS (M+NH₄ ⁺): 262.

EXAMPLE 93B 6-(4-aminophenyl)-2-naphthalenecarboximidamide,bis(trifluoroacetate) salt

The desired compound is obtained from the material prepared in Example93A (0.1 g, 0.41 mmol) using the procedure described in Example 94DYield: 35 mg, 53%

MS (M+H)⁺ 262; ¹H NMR 300 MHz, (DMSO-d₆): δ 9.45 (bs, 2H), 9.35 (bs,2H), 8.45 (d, 1H), 8.22 (s, 1H), 8.15 (d, 1H), 8.10 (d, 1H), 7.99 (dd,1H), 7.79 (dd, 1H), 7.65 (d, 2H), 6.95 (d, 2H), 4.80 (bs, 3H); Anal.calc'd: C₂₁H₁₇N₃O₆F₆: C, 51.54, H, 3.50, N, 8.59, Found: C, 51.95, H,3.84.

EXAMPLE 95 Methyl2-[4-[[[6-(aninoiminomethyl)-2-naphthalenyl]carbonyl]amino]phenoxy]acetate,mono(trifluoroacetate) salt EXAMPLE 95A

4-Acetamidophenol (5 g, 33 mmol) is dissolved in THF (100 mL) treatedwith Cesium carbonate (10.25 g, 33 mmol) and Methyl bromoacetate (3.4mL, 36 mmol) and stirred 24 hours at room temperature. The reactionmixture is diluted with water (100 mL) and concentrated under vacuum.The residue is dissolved in ethyl acetate (100 mL) washed with 1 N H₃PO₄(20 mL), saturated NaHCO₃ (20 mL), 10% NaCl (20 mL) and dried overanhydrous Na₂SO₄. The drying agent is filtered and the solvent removedunder vacuum leaving the desired compound as a white solid, 6.8 g,(92%).

MS (M+NH₄ ⁺): 241.

EXAMPLE 95B

The material obtained in Example 95A is treated with 2 N HCl (75 mL) andrefluxed for 3 hours. The clear mixture is cooled to room temperaturethen concentrated under vacuum to an off white solid as the desiredcompound. 6 g, 92%.

MS (M+NH₄ ⁺): 198.

EXAMPLE 95C

6-carboxy-2-naphthonitrile (0.1 g, 0.51 mmol) is dissolved in DMF (5 mL)cooled in an ice bath to 5° C. To the homogeneous mixture is addedDiisopropylethylamine (0.18 mL, 1.05 mmol) andO-(7-Azabenzotriazol-1-yl)-N, N, N′, N′-tetramethyluroniumhexafluorophosphate (HATU). The resultant slurry is stirred at 5° C. 45minutes. To this slurry is added the material obtained in Example 95B(0.12 g, 0.56 mmol) and the mixture is stirred at room temperatureovernight. The next day, the reaction mixture is diluted with ethylacetate (100 mL) washed with 1 N H₃PO₄ (20 mL), saturated NaHCO₃ (20mL), 10% NaCl, dried over anhydrous Na₂SO₄ filtered and solvent removedunder vacuum yielding the desired compound as a brown solid. 0.28 g,65%.

MS (M+NH₄)⁺: 378.

EXAMPLE 95D Methyl2-[4-[[[6-(aminoiminomethyl)-2-naphthalenyl]carbonyl]amino]phenoxy]acetate,mono(trifluoroacetate) salt

The material obtained in Example 95C (0.28 g, 0.78 mmol) is dissolved inmethanol saturated with HCl (g) (30 mL) stirred 18 hours at roomtemperature. The solvent removed under vacuum and the resultant yellowsolid is treated with 2 M NH₃/methanol (20 mL). This solution isrefluxed 6 hours, cooled, solvent removed under vacuum and the resultingbrown solid is purified by reverse phase HPLC. The desired compound isobtained from lyophilization. 19.3 mg, 20%.

MS (M+H)⁺: 378; ¹HNMR 300 MHz, (DMSO-d₆): δ 10.45 (s, 1H), 9.45 (bs,4H), 8.65 (d, 1H), 8.59 (s, 1H), 8.15 (d, 1H), 8.10 (d, 1H), 8.08 (d,1H), 7.92 (d, 1H), 7.75 (d, 2H), 6.98 (d, 2H), 4.80 (s, 2H), 3.75 (s,3H), Anal. calc'd: C₂₃H₂₁N₃O₆F₃: C, 56.10, H, 4.3, N, 8.53, Found: C,55.80, H, 3.93, N, 8.33.

EXAMPLE 96(E)-6-[2-[(3-hydroxymethyl)phenyl]ethenyl]-2-naphthalenecarboximidamide,mono(trifluoroacetate)(salt) EXAMPLE 96A

The above was prepared from 3-iodobenzyl alcohol using the procedure inExample 41A.

MS (DCI/NH₃) m/z (M+NH₃)⁺ 303.

EXAMPLE 96B(E)-6-[2-[(3-hydroxymethyl)phenyl]ethenyl]-2-naphthalenecarboximidamide,mono(trifluoroacetate)(salt)

The above was prepared from Example 96A using method from Example 40D.

MS (DCI/NH₃) m/z (M+H)⁺ 303; ¹H-NMR (300 MHz, DMSO-d₆) δ 9.18 (br, 4H),8.45 (s, 1H), 8.17 (s, 1H), 8.13-8.04 (m, 3H), 7.81 (dd, 1H), 7.64 (s,1H), 7.57 (d, 2H), 7.51 (d, 1H) 7.39 (t, 1H), 7.28 (d, 1H), 5.27 (t,1H), 4.55 (d, 2H); Anal. calc'd for C₂₂H₁₉N₂O₃F₃ 3/10 TFA: C, 60.64; H,4.35; N, 6.28. Found: 4.87; N, 6.57.

EXAMPLE 97 6-(2-phenyl-1-cyclopropyl)-2-naphthalenecarboximidamide,mono(trifluoroacetate)(salt) EXAMPLE 97A

Copper (I) chloride (43 mg, 0.4 mmol), powdered zinc (26 mg, 0.4 mmol)were suspended in 1 mL dioxane for 18 hours. The product from Example41B (60 mg, 0.2 mmol) was added and stirred and heated at 95° C. for 20hours. The reaction mixture was concentrated on silica gel and purifiedby silica gel chromatography to give the desired compound.

MS (DCI/NH₃) m/z (M+NH₃)⁺ 287.

EXAMPLE 97B 6-(2-phenyl-1-cyclopropyl)-2-naphthalenecarboximidamide,mono(trifluoroacetate)(salt)

The above was prepared from Example 1 using method from Example 1B.

MS (DCI/NH₃) m/z (M+H)⁺ 287; ¹H-NMR (300 MHz, DMSO-d₆) δ 9.41 (s, 2H),9.16 (s, 2H), 8.46 (s, 1H), 7.83 (d, 2H), 7.62 (s, 1H), 7.58 (dd, 1H),7.34 (dd, 1H), 7.35-7.29 (m, 3H), 7.25-7.17 (m, 2H) 2.38-2.28 (m, 2H),1.61 (t, 2H); Anal. calc'd for C₂₂H₁₉N₂O₂F₃ 1/10 TFA: C, 65.00; H, 4.70;N, 6.84. Found: C, 65.22; H, 5.23; N, 5.10.

EXAMPLE 98(E)-6-[2-[4-(aminomethyl)phenyl]ethenyl]-2-naphthalenecarboximidamide,bis(trifluoroacetate)(salt) EXAMPLE 98A

The desired compound was prepared using ethene under 500 atm pressure ina manner; Analagous to that of Example 41A.

MS (DCI/NH₃) m/z (M+NH₃)⁺ 197.

EXAMPLE 98B

4-(Aminomethyl)-iodobenzene hydrochloride (1 g, 3.7 mmol) and Bocanhydride (1.22 g, 5.6 mmol) were mixed with 10% NaOH (15 mL), ethylacetate (20 mL) and stirred 2 hours. The organic layer was washed with5% sodium bicarbonate (2×, 10 mL), dried (magnesium sulfate), andconcentrated to give 1.22 g of desired compound.

MS (DCI/NH₃) m/z (M+NH₃)⁺ 351.

EXAMPLE 98C

The desired compound was prepared using the product from Example s 98Aand 98B in a manner analagous to that of Example 41A.

MS (DCI/NH₃) m/z (M+NH₃)⁺ 402.

EXAMPLE 98D(E)-6-[2-[4-(aminomethyl)phenyl]ethenyl]-2-naphthalenecarboximidamide,bis(trifluoroacetate)(salt)

The above product was prepared in a manner analogous to that of Example40D with the addition of trifluoroacetic acid in methylene chloride toremove the Boc group.

MS (DCI/NH₃) m/z (M+H)⁺ 302; ¹H-NMR (300 MHz, DMSO-d₆) δ 9.43 (s, 2H),9.11 (s, 2H), 8.46 (s, 1H), 8.16 (br, 3H), 8.15 (d, 1H), 8.04 (d, 1H),7.82 (dd, 1H), 7.75 (d, 1H), 7.54 (s, 1H) 7.50 (d, 1H), 4.08 (d, 2H);Anal. calc'd for C₂₄H₂₁N₃O₄F₆ 2/5 TFA: C, 50.46; H, 3.63; N, 6.99.Found: C; 50.37; H, 3.86; N, 7.05.

EXAMPLE 99 Methyl[7-(aminoiminomethyl)-2-methoxy-1-naphthalenyl)carbamate,mono(trifluoroacetate)(salt)

The desired compound was prepared using material prepared as describedin Example 90D and utilizing the procedures described in Example 91A andExample 40D.

MS (DCI/NH₃) m/z (M+H)⁺ 306; ¹H-NMR (300 MHz, DMSO-d₆) δ 9.33 (s, 2H),8.98 (s, 2H), 8.63 (s, 1H), 7.99 (d, 1H), 7.60 (dd, 1H), 7.58 (s, 1H),7.54 (d, 1H), 7.35-7.20 (m, 5H), 4.52 (s, 2H); Anal. calc'd forC₂₁H₂₀N₃O₃F₃ 13/5 TFA: C, 44.03; H, 3.19; N, 5.89. Found: C; 43.97; H,3.55; N, 6.10.

EXAMPLE 1007-methoxy-8-(2-pyrimidinylamino)-2-naphthalenecarboximidamide,bis(trifluoroacetate)(salt)

The desired compound was prepared using material prepared as describedin Example 90D and utilizing the procedures described in Example 91A andExample 40D.

MS (DCI/NH₃) m/z (M+H)⁺ 322; ¹H-NMR (300 MHz, DMSO-d₆) δ 9.35 (s, 2H),8.90 (s, 2H), 8.34 (s, 1H), 8.11 (d, 1H), 7.90 (d, 1H), 7.72 (d, 1H),7.60 (dd, 1H), 7.47 (s, 2H), 6.70 (d, 2H) 6.49 (d, 2H), 3.88 (s, 3H),3.64 (s, 3H); Anal. calc'd for C₂₁H₂₀N₃O₄F₃ 1/10 TFA: C, 56.90; H, 4.53;N, 9.38. Found: C; 56.88; H, 4.41; N, 9.43.

EXAMPLE 1017-methoxy-8-[(phenylmethyl)amino]-2-naphthalenecarboximidamide,mono(trifluoroacetate)(salt) EXAMPLE 101A

4-Bromostyrene (4.8 g, 26.2 mmol) was dissolved in 100 mL THF and cooledto −78° C. Butyl lithium (2.5 M in hexanes, 28.8 mmol) was addeddropwise and stirred 5 minutes. Iodine in THF was added dropwise untilan orange/red color persisted. Concentrated aqueous ammonium chloride(20 mL) was added and the reaction was warmed to room temperature,diluted with ether, washed with 10% Na₂S₂O₅ solution (1×, 50 mL), andbrine (1×, 50 mL), dried (magnesium sulfate), and concentrated to givethe desired compound.

MS (DCI/NH₃) m/z 122.

EXAMPLE 101B

The product from 104A (2.35 g, 10.2 mmol), 1.6 mL 60%,N-methylmorphiline-N-oxide/water solution, 3.75 mL acetone, 0.1 mL waterwere stirred 1 hour. 20 mL Osmium tetroxide/tert-butanol solution (0.02mmol/mL) was added and stirred at 0° C. for 20 hours. The reaction wasconcentrated on silica gel and pulled by silica gel chromatography togive the desired compound.

MS (DCI/NH₃) m/z (M+NH₃)⁺ 282.

EXAMPLE 101C

The desired compound from Example 104B is coupled using Method 41A.

MS (DCI/NH₃) m/z (M+NH₃)⁺ 333.

EXAMPLE 101D7-methoxy-8-[(phenylmethyl)amino]-2-naphthalenecarboximidamide,mono(trifluoroacetate)(salt)

The above was prepared from Example 104C using method described inExample 40D.

MS (DCI/NH₃) m/z (M+H)⁺ 333; ¹H-NMR (300 MHz, DMSO-d₆) δ 9.42 (s, 2H),9.12 (s, 2H), 8.45 (s, 1H), 8.15-8.05 (m, 4H), 7.81 (dd, 1H), 7.63 (d,2H), 7.48 (d, 2H), 7.39 (d, 2H), 4.56 (t, 1H), 3.45 (d, 2H); Anal.calc'd for C₂₃H₂₁N₂O₄F₃ 2/5 TFA: C, 58.19; H, 4.39; N, 5.71. Found: C,58.17; H, 4.41; N, 5.87.

EXAMPLE 102 7-methoxy-8-(phenylamino)-2-naphthalenecarboximidamide,mono(trifluoroacetate)(salt) EXAMPLE 102A

Tert-butylcarbamate (3.62 g, 15.7 mmol) was dissolved in 63 mL propanol.118 mL NaOH/water solution (0.4 N), tert-butyl hypochloride (5.5 mL,47.8 mmol), and (DHQD)₂PHAL (612 mg, 0.61 mmol) in 50 mL propanol wereadded and stirred 10 minutes. The product from Example 2 (3.62 g, 15.7mmol), and K₂OsO₄.2 water (211 mg, 0.63 mmol) were added and stirred 24hours. The reaction was concentrated and recrystallized fromethanol/hexanes to give the desired compound.

MS (DCI/NH₃) m/z (M+NH₃)⁺ 381.

EXAMPLE 102B

The above was prepared from Example 102 using the method described inExample 41A.

MS (DCI/NH₃) m/z (M+H)⁺ 415.

EXAMPLE 102C 7-methoxy-8-(phenylamino)-2-naphthalenecarboximidamide,mono(trifluoroacetate)(salt)

The above was prepared from Example 102B using the method described inExample 94D.

MS (DCI/NH₃) m/z (M+H)⁺ 264; ¹H-NMR (300 MHz, DMSO-d₆) δ 9.42 (s, 2H),9.07 (s, 2H), 8.45 (s, 1H), 8.33 (br, 3H), 8.16-8.03 (m, 4H) 7.75 (d,2H), 7.56 (s, 2H), 7.49 (d, 2H), 5.49 (br 1 h), 4.28 (br, 1H), 3.62 (m,2H); Anal. calc'd for C₂₅H₂₃N₃O₅F₆.5TFA: C, 37.30; H, 2.51; N, 3.74.Found: C; 37.06; H, 3.12; N, 4.42.

EXAMPLE 1037-methoxy-8-[(4-methoxyphenyl)amino]-2-naphthalenecarboximidamide,mono(trifluoroacetate)(salt) EXAMPLE 103A

4-Bromobenzaldehyde (600 mg, 3.24 mmol), 16.2 mL dimethylamine in THF(32.4 mmol), and sodium triacetoxyborohydride (1.24 g, 5.8 mmol) weresuspended in dichloroethane (10 mL). The reaction mixture wasconcentrated, diluted with water acidified to pH=2 and extracted withether (3×, 20 mL). The aqueous solution was basified with NaOH/water topH=12 and extracted with methylene chloride (3×, 30 mL, acidified withHCl/methanol and concentrated to give the desired compound.

MS (DCI/NH₃) m/z (M)⁺ 214.

EXAMPLE 103B

The above was prepared from Example 107A using method from Example 41A.

MS (DCI/NH₃) m/z (M+H)⁺ 313.

EXAMPLE 103C7-methoxy-8-[(4-methoxyphenyl)amino]-2-naphthalenecarboximidamide,mono(trifluoroacetate)(salt)

The above was prepared from Example 103 using method from Example 40D.

MS (DCI/NH₃) m/z (M+H)⁺ 294; ¹H-NMR (300 MHz, DMSO-d₆) δ 9.43 (s, 2H),9.11 (s, 2H), 8.46 (s, 1H), 8.18-8.06 (m, 4H), 7.84 (d, 4H), 7.60 (s,2H), 7.56 (s, 1H), 4.53 (s, 2H), 3.05 (s, 6H); Anal. calc'd forC₂₆H₂₅N₃O₄F₆ 7/5 TFA: C, 48.46; H, 3.73; N, 5.91. Found: C, 48.36; H,4.25; N, 6.19.

EXAMPLE 104(E)-6-[2-[4-(1,2-dihdyroxyethyl)phenyl]ethenyl]-2-naphthalenecarboximidamide,mono(trifluoroacetate)(salt) EXAMPLE 104A

The above was prepared from 4-bromobenzyl alcohol and the compoundprepared in Example 98A using the method from Example 41A.

MS (DCI/NH₃) m/z (M+NH₃)⁺ 303.

EXAMPLE 104B(E)-6-[2-[4-(1,2-dihydroxyethyl)phenyl]ethenyl]-2-naphthalenecarboximidamide,mono(trifluoroacetate)(salt)

The above was prepared from Example 104A using method from Example 40D.MS (DCI/NH₃) m/z (M+H)⁺ 303; ¹H-NMR (300 MHz, DMSO-d₆) δ 9.00 (br, 4H),8.44 (s, 1H), 8.15-8.01 (m, 4H), 7.81 (dd, 1H), 7.64 (d, 2H), 7.48 (d,1H), 7.36 (d, 2H), 5.21 (br, 1H) 4.53 (s, 2H); Anal. calc'd forC₂₂H₁₉N₂O₃F₃ 4/5 TFA: C, 55.84; H, 3.93; N, 5.52. Found: C, 55.60; H,3.93; N, 6.41.

EXAMPLE 105(E)-6-[2-[4-(1R-amino-2-hydroxyethyl)phenyl]ethenyl]-2-naphthalenecarboximidamide,bis(trifluoroacetate)(salt) EXAMPLE 105A

Using the procedure described for Example 121A, and substitutingN-BOC-p-iodophenylalanine (BACHEM Bioscience Inc.) for 4-iodoaniline,the desired compound was obtained.

MS (DCI/NH₃) m/z 458 (M+NH₄)⁺; ¹H NMR (300 MHz, CDCl₃) δ 1.35 (s, 9H),2.90 (t, 1H), 3.09 (dd, 1H), 4.15 (m, 1H), 7.20 (d, 1H), 7.36 (d, 2H),7.56 (d, 2H), 7.78 (d, 1H), 7.85 (d, 1H), 8.12 (d, 1H), 8.17 (d, 1H),8.32 (s, 1H), 8.62 (s, 1H).

EXAMPLE 105B

Using the product obtained in Example 105A and the procedure describedin Example 40D the desired compound was obtained.

MS (ESI) m/z 458 (M+H)⁺; ¹H NMR (300 MHz, DMSO) δ 1.35 (s, 9H), 2.90(dd, 1H), 3.10 (dd, 1H), 4.13 (m, 1H), 7.10 (d, 1H), 7.36 (d, 2H), 7.55(d, 2H), 7.78 (dd, 1H), 7.85 (dd, 1H), 8.13 (d, 1H), 8.19 (d, 1H), 8.30(s, 1H), 8.50 (s, 1H), 9.22 (s, 2H), 9.42 (s, 2H).

EXAMPLE 105C(E)-6-[2-[4-(1R-amino-2-hydroxyethyl)phenyl]ethenyl]-2-naphthalenecarboximidamide,bis(trifluoroacetate)(salt)

Using the product obtained in Example 105B and the procedure describedfor Example 124D, the desired compound was obtained.

MS (ESI) m/z 358 (M+H)⁺; ¹H NMR (300 MHz, DMSO) δ 3.02 (m, 1H), 3.19(dd, 1H), 3.63 (t, 1H), 7.39 (d, 2H), 7.58 (d, 2H), 7.76 (d, 1H), 7.88(d, 1H), 8.15 (d, 1H), 8.19 (d, 1H), 8.30 (s, 1H), 8.51 (s, 1H), 9.41(s, 2H), 9.80 (s, 2H); Anal. calc'd for C₂₄H₂₀F₃N₃O₄H₂O: C, 58.90; H,4.53; N, 8.59. Found: C, 58.75; H, 4.22; N, 8.28.

EXAMPLE 1067-methoxy-8-(2-pyrimidinylamino)-2-naphthalenecarboximidamide,bis(trifluoroacetate)(salt) EXAMPLE 106A

Sodium borohydride (0.22 g, 5.8 mmol) was added to a suspension of(4-bromobenzoyl)methanol (2.5 g, 11.6 mmol, Maybridge Chem. Co.) and 25mL abs. ethanol. The reaction mixture was stirred at reflux for 1 hour.After cooling to room temperature, the ethanol was evaporated undervacuum, and water was added to the residue. The mixture was extractedwith CH₂Cl₂. The extracts were washed with saturated aqueous sodiumchloride, dried over MgSO₄, filtered, and evaporated under vacuum toafford the desired compound.

MS (DCI/NH₃) m/z 234/236 (M+NH₄)⁺; ¹H NMR (300 MHz, CDCl₃) δ 2.10 (t,1H), 2.62 (d, 1H), 3.63 (m, 1H), 3.78 (m, 1H), 4.81 (m, 1H), 7.25 (d,2H), 7.50 (d, 2H).

EXAMPLE 106B

Using the product obtained in Example 106A and the procedure describedin Example A-226218-A, the desired compound was obtained.

MS (DCI/NH₃) m/z 331 (M+NH₄)⁺; ¹H NMR (300 MHz, CDCl₃) d3.45 (t, 1H),4.59 (q, 1H), 4.76 (t, 1H), 5.36 (d, 1H), 7.42 (d, 2H), 7.59 (d, 2H),7.78 (dd, 1H), 7.85 (dd, 1H), 8.10 (d, 1H), 8.15 (d, 1H), 8.30 (s, 1H),8.61 (s, 1H).

EXAMPLE 106C7-methoxy-8-(2-pyrimidinylamino)-2-naphthalenecarboximidamide,bis(trifluoroacetate)(salt)

Using the product obtained in Example 106B, and the procedure describedin Example 40D, the desired compound was obtained.

MS (ESI) m/z 331 (M+H)⁺; ¹H NMR (300 MHz, DMSO) δ 3.45 (t, 1H), 4.59 (q,1H), 4.78 (t, 1H), 5.38 (d, 1H), 7.42 (d, 2H), 7.59 (d, 2H), 7.78 (dd,1H), 7.84 (dd, 1H), 8.12 (d, 1H), 8.18 (d, 1H), 8.31 (s, 1H), 8.50 (s,1H), 9.20 (s, 2H), 9.43 (s, 2H); Anal. calc'd for C₂₃H₁₉F₃N₂O₄H₂O: C,59.74; H, 4.58; N, 6.06. Found: C, 59.95; H, 4.17; N, 6.13.

EXAMPLE 107(E)-6-[2-[[4-(dimethylamino)methyl]phenyl]ethenyl]-2-naphthalenecarboximidamide,bis(trifluoroacetate)(salt) EXAMPLE 107A

Using the procedure described for Example 121A, and substituting3-benzyloxybromobenzene (Chem. Ber. 124 (1), 163, 1991) for4-iodoaniline, the desired compound was obtained.

MS (DCI/NH₃) m/z 377 (M+NH₄)⁺; ¹H NMR (300 MHz, CDCl₃) δ 5.11 (s, 2H),7.02 (d, 1H), 7.20 (m, 2H), 7.29 (d, 1H), 7.31 (d, 1H), 7.42 (m, 3H),7.60-7.75 (m, 3H), 7.89 (t, 2H), 8.08 (s, 1H), 8.21 (s, 1H).

EXAMPLE 107B(E)-6-[2-[[4-(dimethylamino)methyl]phenyl]ethenyl]-2-naphthalenecarboximidamide,bis(trifluoroacetate)(salt)

Using the product obtained in Example 108B, and the procedure describedin Example 40D, the desired compound was obtained.

MS (ESI) m/z 377 (M+H)⁺; ¹H NMR (300 MHz, DMSO) δ 5.18 (S, 2H), 7.12(dd, 1H), 7.22 (d, 1H), 7.28 (m, 1H), 7.40 (t, 3H), 7.45 (t, 3H), 7.79(dd, 1H), 7.85 (dd, 1H), 8.16 (d, 1H), 8.20 (d, 1H), 8.35 (s, 1H), 8.50(s, 1H), 9.30 (s, 1H); Anal. calc'd for C₂₈H₂₁F₃N₂O₃.0.25 H₂O: C, 67.94;H, 4.38; N, 5.66. Found: C, 67.80; H, 4.48; N, 5.43.

EXAMPLE 108(E)-6-[2-[4-(hydroxymethyl)phenyl]ethenyl]-2-naphthalenecarboximidamide,mono(trifluoroacetate)(salt)

Using the product obtained in Example 108A and the procedure describedin Example 94D the desired compound was obtained.

MS (ESI) m/z 287 (M+H)⁺; ¹H NMR (300 MHz, DMSO) δ 6.89 (m, 1H), 6.98 (t,1H), 7.03 (d, 1H), 7.29 (t, 1H), 7.78 (dd, 1H), 7.88 (dd, 1H), 8.13 (d,1H), 8.17 (d, 1H), 8.32 (s, 1H), 8.50 (s, 1H), 9.40 (s, 5H); Anal.calc'd for C₂₁H₁₅F₃N₂O₃0.5 H₂O: C, 61.62; H, 3.94; N, 6.84. Found: C,61.29; H, 3.81; N, 6.59.

EXAMPLE 1094-[[6-(aminoiminomethyl)-2-naphthalenyl]ethynyl]-L-phenylalanine,mono(trifluoroacetate)(salt) EXAMPLE 109A

To a solution of the product from Example 8D (2.13 g, 10.08 mmol) andLiBH₄ (121 mg, 5.55 mmol) in THF (5 mL) was added toluene (2 mL), andthe THF was boiled off using a short-path distillation apparatus overseveral hours. The reaction was then heated at 70° C. for 2 hours,cooled, quenched with 1 M HCl, and extracted with 2× ethyl acetate. Theextracts were washed with water and brine, dried over Na₂SO₄, andcondensed. The crude product was chromatographed on SiO₂ using 50% ethylacetate/hexanles as eluent, to yield 1.12 g (61%) of the desiredcompound.

MS (DCI (NH₃)) m/z 201 (M+NH₄)⁺; ¹H NMR (300 MHz, CDCl₃) δ 8.22 (s, 1H),7.90 (m, 3H), 7.61 (m, 2H), 4.92 (d, 2H), 1.84 (t, 1H).

EXAMPLE 109B

To a solution of the product from Example 109A (2.12 g, 11.57 mmol) andLiBr (1.11 g, 12.73 mmol) in DMF (100 mL) was added PBr₃ (1.21 mL, 12.73mmol) at 0° C., and the reaction was warmed to room temperature, andstirred for 1 hours. The reaction was then quenched with pH 7 buffer,and extracted with 3× dimethyl ether/hexanes. The extracts were washedwith 2× water and 2× brine, dried over Na₂SO₄, and condensed, to yield2.72 g (96%) of the desired compound.

MS (DCI (NH₃)) m/z 185 (M+NH_(4-Br))⁺; ¹H NMR (300 MHz, CDCl₃) δ 8.22(s, 1H), 7.92 (s, 1H), 7.90 (s, 2H), 7.62 (dd, 2H), 4.64 (s, 2H).

EXAMPLE 109C

To a solution of NaH (60% in mineral oil, 44 mg, 1.1 mmol) in DMF (5 mL)was added 4-ethylphenol (122 mg, 1.0 mmol), and the reaction was stirredat room temperature for 20 minutes. The product from Example 109B (270mg, 1.1 mmol) was then added, and the reaction was stirred for 10minutes. The crude reaction mixture was chromatographed on SiO₂ usinghexanes as eluent, to yield 220 mg (77%) of the desired compound.

MS (DCI (NH₃)) m/z 305 (M+NH₄)⁺; ¹H NMR (300 MHz, CDCl₃) δ 8.22 (s, 1H),7.95 (s, 1H), 7.93 (s, 1H), 7.91 (s, 1H), 7.66 (dd, 1H), 7.61 (dd, 1H),7.15 (d, 2H), 6.94 (d, 2H), 5.22 (d, 2H), 2.60 (q, 2H), 1.21 (t, 3H).

EXAMPLE 109D 4-[[6-(aminoiminomethyl)-2-naphthalenyl]ethynyl]-L-phenylalanine,mono(trifluoroacetate)(salt)

The desired compound was prepared from Example 109C and the procedure ofExample 55D.

MS (DCI/NH₃) m/z 305 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆) δ 1.15 (t, 3H),2.14 (s, 3H), 2.56 (q, 2H), 5.30 (s, 2H), 6.98 (d, 2H), 7.14 (d, 2H),7.74 (dd, 1H), 7.82 (dd, 1H), 8.15 (m, 3H), 8.48 (s, 1H), 9.01 (br s,2H), 9.62 (br s, 2H); Anal. calc'd for C₂₀H₂₀N₂O.1.4 CH₄SO₃: C, 58.56;H, 5.88; N, 6.38. Found: C, 58.55; H, 5.56; N, 6.39.

EXAMPLE 111 6-(3-formylphenyl)-2-naphthalenecarboximidamide,mono(trifluoroacetate)(salt) EXAMPLE 111A

The product from Example 28B (334 mg, 1.11 mmol), palladium acetate (25mg, 0.11 mmol), dppf (123 mg, 0.22 mmol) were dissolved in degassed DMF(5 mL) and stirred at room temperature for ½ hour. Cesium carbonate (902mg, 2.8 mmol) and 2-formylphenylboronic acid (251 mg, 1.27 mmol) wereadded and stirred under nitrogen at 80° C. for 1 hour, poured into pH 7buffer, extrated with diethyl ether (3×, 20 mL), and dried. The desiredcompound was purified by chromotography eluting with 10% ethylacetate/hexanes.

MS (DCI/NH₃) m/z (M+NH₃)⁺ 275.

EXAMPLE 111B 6-(3-formylphenyl)-2-naphthalenecarboximidamide,mono(trifluoroacetate)(salt)

The above product was prepared in a manner analogous to that of Example1B.

MS (DCI/NH₃) m/z (M+H)⁺ 274; ¹H-NMR (300 MHz, DMSO-d₆) δ 10.16 (s, 1H),9.47 (s, 2H), 9.10 (s, 2H), 8.54 (s, 1H), 8.52 (s, 1H), 8.41 (s, 1H),8.28-8.23 (m, 3H), 8.12 (dd, 1H), 8.00 (dd, 1H), 7.87 (dd, 1H), 7.80 (t,1H); Anal. calc'd for C₂₀H₁₅N₂O₃F₃ 2/5 TFA: C, 59.28; H, 3.70; N, 6.34.Found: C; 59.36; H, 3.89; N, 7.21.

EXAMPLE 112(E)-6-[2-(1,2,3,4-tetrahydro-6-isoquinolinyl)ethenyl]-2-naphthalenecarboximidamide,bis(trifluoroacetate)(salt) EXAMPLE 112A

The above was prepared from Example 127 using method described inExample 41A.

MS (DCI/NH₃) m/z (M+H)⁺ 411.

EXAMPLE 112B(E)-6-[2-(1,2,3,4-tetrahydro-6-isoquinolinyl)ethenyl]-2-naphthalenecarboximidamide,bis(trifluoroacetate)(salt)

The desired compound was prepared by the method described in Example40D.

MS (DCI/NH₃) m/z (M+H)⁺ 328; ¹H-NMR (300 MHz, DMSO-d₆) δ 9.36 (s, 2H),9.25 (s, 2H), 9.10 (d, 2H), 8.41 (s, 1H), 7.99 (t, 2H), 7.89 (d, 1H),7.78 (d, 1H), 7.71 (dd, 1H), 7.56 (m, 4H), 7.43 (s, 1H), 3.11 (br, 2H)2.16 (br 2H), 1.78 (br, 2H); Anal. calc'd for C₂₆H₂₃N₃O₄F₆ 3/5 TFA: C,52.31; H, 3.81; N, 6.72. Found: C, 52.13; H, 4.42; N, 7.23.

EXAMPLE 113(E)-6-[2-[3-(2-hydroxyethyl)phenyl]ethenyl]-2-naphthalenecarboximidamide,mono(trifluoroacetate)(salt) EXAMPLE 113A

The above was prepared from 2-bromo-3 (hydroxyethyl)alcohol and thecompound prepared in Example 98A using method described in Example 41A.

MS (DCI/NH₃) m/z (M+NH₃)⁺ 317.

EXAMPLE 113B(E)-6-[2-[3-(2-hydroxyethyl)phenyl]ethenyl]-2-naphthalenecarboximidamide,mono(trifluoroacetate)(salt)

The above was prepared from Example 113A using method described inExample 40D.

MS (DCI/NH₃) m/z (M+H)⁺ 317; ¹H-NMR (300 MHz, DMSO-d₆) δ 8.9 (br, 4H),8.46 (s, 1H), 8.17 (s, 1H), 8.13-8.03 (m, 3H), 7.82 (dd, 1H), 7.54 (s,2H), 7.49 (s, 2H), 7.33 (t, 1H) 7.18 (d, 1H), 4.71 (t, 1H), 3.66 (m,2H), 2.78 (t, 2H); Anal. calc'd for C₂₃H₂₁N₂O₃F₃ 3/10 TFA: C, 61.41; H,4.66; N, 6.09. Found: C, 64.18; H, 4.92; N, 6.51.

EXAMPLE 1146-(aminoiminomethyl)-4-(3-furanyl)-N-[4-(trifluoromethyl)phenyl]-2-naphthalenecarboxamide,mono(trifluoroacetate)(salt) EXAMPLE 114A

The product from Example 152B (100 mg, 0.36 mmol),4-(trifluoromethyl)aniline (86 mg, 0.53 mmol), and DMAP (5 mg, 0.04mmol) were dissolved in THF (5 mL) and stirred for 24 hours. Thereaction mixture was concentrated on silica gel and purified bychromotography (Biotage Flash 40) using ethyl acetate/hexanes.

MS (ESI) m/z (M+H)⁺ 406.

EXAMPLE 114B6-(aminoiminomethyl)-4-(3-furanyl)-N-[4-(trifluoromethyl)phenyl]-2-naphthalenecarboxamide,mono(trifluoroacetate)(salt)

The above was prepared from Example 114A using method described inExample 1B.

MS (CI) m/z (M+H)⁺ 424; ¹H-NMR (300 MHz, DMSO-d₆) δ 10.91 (s, 1H), 9.51(s, 2H), 9.11 (s, 2H), 8.69 (s, 1H), 8.62 (s, 1H), 8.43-8.35 (m, 2H),8.18 (d, 1H), 8.06 (d, 2H), 7.98 (t, 1H), 7.92 (dd, 1H), 7.78 (dd, 2H)7.14 (m, 1H); Anal. calc'd for C₂₅H₁₇N₃O₄F₆ 1/10 TFA: C, 55.37; H, 3.15;N, 7.70. Found: C, 55.44; H, 3.15; N, 7.31.

EXAMPLE 1156-(aminoiminomethyl)-4-(3-furanyl)-N-(4-pyridinyl)-2-naphthalenecarboxamide,dihydrochloride EXAMPLE 115A

The above product was prepared in the maniner of Example 114A.

MS (ESI) m/z (M+H)⁺ 340.

EXAMPLE 115B6-(aminoiminomethyl)-4-(3-furanyl)-N-(4-pyridinyl)-2-naphthalenecarboxatide,dihydrochloride

The above was prepared from Example 115A using method described inExample 1B.

MS (AP/Cl) m/z (M+H)⁺ 357; ¹H-NMR (300 MHz, DMSO-d₆) δ 12.43 (s, 1H),9.69 (s, 2H), 9.40 (s, 2H), 8.94 (s, 1H), 8.81 (d, 2H), 8.65 (s, 1H),8.58-8.56 (m, 2H), 8.49 (s, 1H), 8.42 (d, 1H), 8.30 (m, 1H), 7.97-7.95(m, 2H), 7.27 (s, 1H); Anal. calc'd for C₂₁H₁₈N₄O₂Cl₂ 37/10 HCl: C,44.65; H, 3.88; N, 9.92. Found: C, 44.72; H, 3.70; N, 9.51.

EXAMPLE 1166-(aminoiminomethyl)-4-(3-furanyl)-N-(1H-pyrazol-3-yl)-2-naphthalenecarboxamide,dihydrochloride EXAMPLE 116A

The above product was prepared in the maniner of Example 114A.

MS (ESI) m/z (M+H)⁺ 329.

EXAMPLE 116B6-(aminoiminomethyl)-4-(3-furanyl)-N-(1H-pyrazol-3-yl)-2-naphthalenecarboxamide,dihydrochloride

The above was prepared from Example 116A using method described inExample 1B.

MS (CI) m/z (M−H)⁺ 344; ¹H-NMR (300 MHz, DMSO-d₆) δ 11.16 (s, 1H), 9.52(s, 2H), 9.10 (s, 2H), 8.69 (s, 1H), 8.61 (s, 1H), 8.35 (m, 2H), 8.24(s, 1H), 7.96-7.88 (m, 3H), 7.69 (m, 1H), 7.15 (s, 1H), 6.69 (m, 1H);Anal. calc'd for C₁₉H₁₇N₅O₂Cl₂ 9/10 HCl: C, 50.63; H, 4.00; N, 15.54.Found: C, 51.05; H, 4.62; N, 14.26.

EXAMPLE 1176-(aminoiminomethyl)-4-(3-furanyl)-N-(3-pyridinyl)-2-naphthalenecarboxamide,dihydrochloride EXAMPLE 117A

The above product was prepared in the manner of Example 114A.

MS (ESI) m/z (M+H)⁺ 340.

EXAMPLE 117B6-(aminoiminomethyl)-4-(3-furanyl)-N-(3-pyridinyl)-2-naphthalenecarboxamide,dihydrochloride

The above was prepared from Example 117B using method described inExample 1B.

MS (CI) m/z (M+H)⁺ 357; ¹H-NMR (300 MHz, DMSO-d₆) δ 10.90 (s, 1H), 9.59(s, 2H), 9.26 (s, 2H), 9.03 (s, 2H), 8.74 (s, 1H), 8.63 (s, 1H),8.42-8.26 (m, 3H), 8.22 (s, 1H), 7.97-7.91 (m, 2H), 7.47-7.43 (m, 2H),7.17 (s, 1H); Anal. calc'd for C₂₁H₁₈N₄O₂Cl₂ 55/10 HCl: C, 40.00; H,3.76; N, 8.89. Found: C, 40.09; H, 3.78; N, 8.44.

EXAMPLE 1186-(aminoiminomethyl)-N-(2,3-dihydro-1H-inden-5-yl)-2-naphthalenecarboxamide,mono(trifluoroacetate)(salt) EXAMPLE 118A

To a solution of the compound prepared in Example 8E (303 mg, 1.4 mmol)in THF (30 mL) and propylene oxide (15 mL) was added two drops of Et₃Nfollowed by the 5-aminoindene (300 mg, 2.2 mmol). The reaction wasstirred at room temperature overnight. The solvent was evaporated andthe product was purified via crystallization from ether to yield 226 mg(56%) of the product as white solid. Mass spectrum (CI+), 313 (M+1)⁺.

EXAMPLE 118B6-(aminoiminomethyl)-N-(2,3-dihydro-1H-inden-5-yl)-2-naphthalenecarboxamide,mono(trifluoroacetate)(salt)

The compound prepared in Example 118A (205 mg, 0.66 mmol) in THF (20 mL)at room temperature, was added butyl lithium (1 mL, 1 mmol) followed bychlorotrimethyl silane (180μL, 1.5 mmol). After 10 minutes the mixturewas charged with additional butyl lithium (3 mL, 3 mmol). The reactionwas stirred at room temperature, overnight. The reaction mixture wasadded a solution of 4 N HCl in dioxane stirred for an hour then addedwater and evaporated. The product was purified by MPLC RP C₁₈ withmethanol-water and 0.1% TFA as eluent chromatography. The yield of theproduct as TFA salt with 0.25% water as white solid 51 mg (17%).

MS (ESI+) 330 (M+1)⁺; ¹H NMR (DMSO-d6) 10.45 (s, 1H), 9.51 (s, 2H), 9.21(s, 2H), 8.66 (s, 1H), 8.55 (s, 1H), 8.32 (d, J=8.5 Hz, 1H), 8.20 (Abq,J=9.0 Hz, 2H), 7.90 (dd, J₁=9.0 Hz, J₂=1.5 Hz, 1H), 7.73 (s, 1H), 7.53(dd, J₁=8.0 Hz, J₂=1.5 Hz, 1H), 7.22 (d, J=8.1 Hz, 1H), 2.91-2.82 (m,4H), 2.04 (quintet, J=7.3 Hz, 2H); Anal. calc'd for C₂₁H₁₉N₃O.TFA.0.25H₂O C: 61.67; H, 4.61; N, 9.38. Found: C: 61.63; H, 4.43; N, 9.25.

EXAMPLE 119 Methyl5-[7-[(aminoiminomethyl)-2-naphthalenyl]oxy]pentanoate,mono(trifluoroacetate) (salt) EXAMPLE 119A 7-hydroxy-2-cyanonaphthalene

7-methoxy-2-cyanonaphthalene (2.79 g, 5.23 mmol) and tetrabutylammoniumiodide (17 mg, 0.157 mmol) were combinied in a mixture of benzene (35mL) and cyclohexanes (17.5 mL). The resulting solution was added to arapidly stirring, cooled (ice/water) suspension of aluminum triiodide(6.21 g, 15.23 mmol) in a mixture of benzene (35 mL) and cyclohexanes(17.5 mL) under an inert atmosphere. After the addition, the resultingsuspension was heated at reflux for 2.5 hours. The heating was removedand after cooling to near room temperature, the reaction mixture wascooled in an ice bath and quenched by the addition of water (100 mL).The resulting mixture was further diluted with 2 M aqueous sodiumthiosulfate solution (50 mL) and extracted with ethyl acetate (3×80 mL).The combined organic layers were dried and evaporated. The resultingsolid was dissolved in a minimum of hot ethyl acetate, diluted hot withhexanes to the cloud point and placed in a refrigerator for 2 hours. Thedesired compound was collected by filtration, (1.99 g, 77%).

MS (DCI (NH₃)) m/z 187 (M+NH₄)⁺.

EXAMPLE 119B

The resulting product from Example 119A was treated with methyl5-bromovalerate in an analogous manner as described in Example 119A.

MS (DCI (NH₃)) m/z 301 (M+NH₄)⁺.

EXAMPLE 119C Methyl5-[7-[(aminoiminomethyl)-2-naphthalenyl]oxy]pentanoate,mono(trifluoroacetate) (salt)

The resulting product from Example 119B (380(mg, 1.3412 mmol) wastreated in an analogous manner as described in Example 94D to yield thedesired compound (369 mg, 73%).

MS (DCI (NH₃)) m/z 301 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆) δ 1.785 (m,4H), 2.425 (t, 2H), 3.600 (s, 3H), 4.150 (t, 2H), 7.380 (dd, 1H), 7.460(d, 1H), 7.640 (dd, 1H), 7.980 (d, 1H), 8.070 (d, 1H), 8.322 (d, 1H),9.230 (v br s, 3H); Anal. calc'd for C₁₇H₂₀N₂O₃C₂HO₂F₃: C, 55.07; H,5.11; N, 6.76. Found: C, 54.96; H, 5.22; N, 6.66.

EXAMPLE 120(E)-3-[7-(aminoiminomethyl)-2-methoxy-1-naphthalenyl)-2-propenamide,mono(trifluoroacetate)(salt) EXAMPLE 120A

The product obtained from Example 53B and acrylamide were subjected tothe conditions described in Example 41A to provide the desired compound.

MS (DCI/NH₃) m/z 253 (M+H)⁺.

EXAMPLE 120B(E)-3-[7-(aminoiminomethyl)-2-methoxy-1-naphthalenyl)-2-propenamide,mono(trifluoroacetate)(salt)

The product obtained from Example 120A was subjected to the conditionsdescribed in Example 94D to provide the desired compound.

MS (DCI/NH₃) m/z 270 (M+H)⁺; ¹H NMR (300 MHz, DMSO) δ 4.02 (s, 3H), 6.90(d, 1H), 7.22 (s, 1H), 7.62-7.70 (m, 2H), 7.74 (d, 1H), 8.02 (d, 1H),8.11 (d, 1H), 8.15 (d, 1H), 8.58 (s, 1H), 9.18 (s, 2H), 9.50 (s, 2H);Anal. calc'd for C₁₇H₁₆F₃N₃O₄H₂O: C, 50.88; H, 4.52; N, 10.47. Found: C,50.89; H, 4.32; N, 10.43.

EXAMPLE 121 6-[(4-aminophenyl)ethynyl]-2-napthalenecarboximidamidebis(trifluoroacetate)(salt) EXAMPLE 121A

A mixture of the product obtained in Example 63B (130 mg, 0.73 mmol),4-iodoaniline (173 mg, 0.79 mmol), dichlorobis(triphenylphosphine)palladium (II) (25 mg, 0.0325 mmol), copper (I)iodide (2.7 mg, 0.0186 mmol), DMF (0.65 mL), and trimethylamine (1.95mL) was degassed with N₂ and was stirred at 75°-80° for 1.5 hour. Themixture was cooled to room temperature, diluted with CH₂Cl₂, washed withwater, dried (MgSO₄), filtered, and evaporated under vacuum to afford anoil which was purified by flash chromatography, eluting with 3:1hexanes: ethyl acetate to afford the desired compound.

MS (DCI/NH₃) m/z 269 (M+H)⁺.

EXAMPLE 121B 6-[(4-aminophenyl)ethynyl]-2-naphthalenecarboximidamide,bis(trifluoroacetate)(salt)

Using the product obtained in Example 121A and the procedure describedin Example 40D, the desired compound was obtained.

MS (DCI/NH₃) m/z 286 (M+H)⁺; ¹H NMR (300 MHz, DMSO) δ 6.80 (d, 2H), 7.29(d, 2H), 7.70 (dd, 1H), 7.85 (dd, 1H), 8.09 (d, 1H), 8.14 (d, 1H), 8.20(s, I1H), 8.45 (s, 1H), 9.09 (s, 2H), 9.42 (s, 2H); Anal. calc'd forC₂₃H₁₇F₆N₃O₄.0.25 H₂O: C, 53.34; H, 3.41; N, 8.11. Found: C, 53.45; H,3.70; N, 7.76.

EXAMPLE 122 1,1-dimethylethyl[2-[3-[[6-(aminoiminomethyl)-2-naplhathalenyl]ethynyl]-6-methoxyphenyl]ethyl]carbamate,mono(trifluoroacetate)(salt) EXAMPLE 122A

Using 5-bromo-2-methoxyphenethylamine hydrobromide (Transworld), and theprocedure described in Example 63C, the desired compound was obtained.

MS (DCI/NH₃) m/z 330 (M+H)⁺.

EXAMPLE 122B

Using the procedure described for Example 121A, and substituting theproduct obtained in Example 122A for 4-iodoanililne, the desiredcompound was obtained.

MS (ESI) m/z 427 (M+H)⁺.

EXAMPLE 122C 1,1-dimethylethyl[2-[3-[[6-(aminoiminomethyl)-2-naphathalenyl]ethynyl]6-methoxyphenyl]ethyl]carbamate,mono(trifluoroacetate)(salt)

Using the product obtained in Example A-226638-B and the proceduredescribed in Example 40-D, the desired compound was obtained.

MS (DCI/NH₃) m/z 444 (M+H)⁺; ¹H NMR (300 MHz, DMSO) δ 1.38 (s, 9H), 2.70(t, 2H), 3.15 (q, 2H), 3.85 (s, 3H), 6.89 (t, 1H), 7.04 (d, 1H), 7.37(d, 1H), 7.49 (dd, 1H), 7.75 (dd, 1H), 7.85 (dd, 1H), 8.11 (d, 1H), 8.16(d, 1H), 8.30 (s, 1H), 8.48 (s, 1H), 9.07 (s, 2H), 9.42 (s, 2H); Anal.calc'd for C₂₉H₃₀F₃N₃O₅.0.25 H₂O: C, 61.97; H, 5.47; N, 7.48. Found: C,61.81; H, 5.14; N, 7.21.

EXAMPLE 123 1,1-dimethylethyl[[4-[[6-(aminoiminomethyl)-2-naphathalenyl]ethynyl]phenyl]methyl]carbamate,mono(trifluoroacetate)(salt) EXAMPLE 123A

Using 4-bromonbenzylamine, and the procedure described in Example 63C,the desired compound was obtained.

MS (DCI/NH₃) m/z 303 (M+NH₄)⁺.

EXAMPLE 123B

Using the procedure described for Example 121A, and substituting theproduct obtained in Example 123 for 4-iodoaniline, the desired compoundwas obtained.

MS (DCI/NH₃) m/z 400 (M+NH₄)⁺.

EXAMPLE 123C 1,1-dimethylethyl[[4-[[6-(aminoiminomethyl)-2-naphathalenyl]ethynyl]phenyl]methyl]carbamate,mono(trifluoroacetate)(salt)

Using the product obtained in Example 123B and the procedure describedin Example 40D, the desired compound was obtained.

MS (DCI/NH₃) m/z 400 (M+H)⁺; ¹H NMR (300 MHz, DMSO) δ 1.40 (s, 9H), 4.18(d, 2H), 7.34 (d, 2H), 7.45 (t, 1H), 7.58 (d, 2H), 7.78 (dd, 1H), 7.86(dd, 1H), 8.15 (d, 1H), 8.19 (d, 1H), 8.31 (s, 1H), 8.50 (s, 1H),9.10-9.42 (s, 4H); Anal. calc'd for C₂₇H₂₆F₃N₃O₄: C, 63.15; H, 5.10; N,8.18. Found: C, 62.95; H, 4.97; N, 8.09.

EXAMPLE 1246-[[4-(aminomethyl)phenyl]ethynyl]-2-naphthalenecarboximidamide,bis(trifluoroacetate)(salt)

Trifluoroacetic acid (0.73 mL) was added dropwise to a suspension of theproduct obtained in Example 123C (80 mg, 0.2 mmol) and 1.5 mL CH₂Cl₂.The reaction mixture was stirred for 0.25 hour at room temperature, thenwas evaporated to dryness under vacuum. Toluene was added and evaporatedunder vacuum several times to afford a tan solid which was purified byreverse phase chmomatography, eluting with methanol/0.1% aqueous TFA toafford the desired compound.

MS (APCI) m/z 300 (M+H)⁺; ¹H NMR (300 MHz, DMSO) δ 4.10 (s, 2H), 7.55(d, 2H), 7.70 (d, 2H), 7.79 (dd, 1H), 7.89 (dd, 1H), 8.16 (d, 1H), 8.19(d, 1H), 8.20 (s, 2H), 8.36 (s, 1H), 8.53 (S, 1H), 9.20 (s, 2H), 9.44(s, 2H); Anal. calc'd for C₂₄H₁₉F₆N₃O₄: C, 54.66; H, 3.63; N, 7.97.Found: C, 54.42; H, 3.57; N, 7.76.

EXAMPLE 1256-[[3-(2-aminoethyl)-4-methoxyphenyl]ethynyl]-2-naphthalenecarboximidamide,bis(trifluoroacetate)(salt)

Using the product obtained in Example 122C and the procedure describedfor Example 124, the desired compound was obtained.

MS (ESI) m/z 344 (M+H)⁺; ¹H NMR (300 MHz, DMSO) δ 2.90 (t, 2H), 3.06 (t,2H), 3.88 (s, 3H), 7.11 (d, 1H), 7.44 (d, 1H), 7.57 (dd, 1H), 7.75 (dd,1H), 7.82 (s, 2H), 7.88 (dd, 1H), 8.12 (d, 1H), 8.17 (d, 1H), 8.28 (s,1H), 8.50 (s, 1H), 9.20 (s, 2H), 9.45 (s, 2H); Anal. calc'd forC₂₆H₂₃F₆N₃O₅.0.5 H₂O: C, 53.80; H, 4.17; N, 7.24. Found: C, 53.89; H,4.31; N, 6.83.

EXAMPLE 1266-[[4-(hydroxymethyl)phenyl]ethynyl]-2-naphthlalenecarboximidamide,mono(trifluoroacetate)(salt) EXAMPLE 126A

Using the procedure described for Example 121A, and substituting4-bromobenzyl alcohol for 4-iodoaniliine, the desired compound wasobtained.

MS (DCI/NH₃) m/z 301 (M+NH₄)⁺.

EXAMPLE 126B6-[[4-(hydroxymethyl)phenyl]ethynyl]-2-naphthalenecarboximidamide,mono(trifluoroacetate)(salt)

Using the product obtained in Example 126A and the procedure describedin Example 94B the desired compound was obtained.

MS (ESI) m/z 301 (M+H)⁺; ¹H NMR (300 MHz, DMSO) δ 4.58 (d, 2H), 5.32 (t,1H), 7.41 (d, 2H), 7.59 (d, 1H), 7.79 (dd, 1H), 7.86 (dd, 1H), 8.12 (d,1H), 8.18 (d, 1H), 8.32 (s, 1H), 8.50 (s, 1H), 9.14 (s, 2H), 9.46 (s,2H); Anal. calc'd for C₂₂H₁₇F₃N₂O₃.0.5 H₂O: C, 62.41; H, 4.29; N, 6.62.Found: C, 62.56; H, 4.13; N, 6.65.

EXAMPLE 1276-[(1,2,3,4-tetrahydro-6-isoquinolinyl)ethynyl]-2-naphthalenecarboximidamide,bis(trifluoroacetate)(salt) EXAMPLE 127A

A solution of boron tribromide (1.2 mL, 12.5 mmol) and 12.5 mL CH₂Cl₂was added dropwise to a −78° solution of6-methoxytetralhydroisoquinoline (1.0 g, 5.0 mole, Org. Synth., 67, 60,1988) and 38 mL CH₂Cl₂. The reaction mixture was stirred for 1 hour at−78°, 1 hour at 0°, and 0.25 hour at room temperature. The reactionmixture was cooled to −78°, and 20 mL methanol was added dropwise. Thesolution was stirred for 1 hour at room temperature. Solvent wasevaporated under vacuum and the residue was dried under vacuum to affordthe desired compound.

MS (DCI) m/z 150 (M+H)⁺.

EXAMPLE 127B

The product obtained in Example 127A (1.15 g, 5.0 mmol) was subjected tothe conditions described in Example 63C. A 2.1 g portion of thismaterial was stirred at reflux for 1.5 hour with 60 mL methanol and 9 mL10% aqueous NaOH. After cooling to room temperature, methanol wasevaporated under vacuum. Water was added and the solution was acidifiedwith 6 N HCl. The mixture was extracted with CH₂Cl₂. The organic layerwas washed with water, saturated aqueous sodium chloride, dried (MgSO₄),filtered, and solvent evaporated under vacuum to afford the desiredcompound.

MS (DCI/NH₃) m/z 267 (M+NH₄)⁺.

EXAMPLE 127C

Using the product from Example 127B and the procedure described inExample 28B, the desired compound was obtained.

MS (DCI/NH₃) m/z 399 (M+NH₄)⁺.

EXAMPLE 127D

Using the procedure described for Example 121A, and substituting theproduct obtained in Example 127C for 4-iodoaniline, the desired compoundwas obtained.

MS (DCI/NH₃) m/z 426 (M+NH₄)⁺.

EXAMPLE 127E

Using the product obtained in Example 127D and the procedure describedin Example 40D, the desired compound was obtained.

MS (ESI) m/z 426 (M+H)⁺; ¹H NMR (300 MHz, DMSO) δ 1.45 (s, 9H), 2.82 (t,2H), 3.59 (t, 2H), 4.58 (s, 2H), 7.29 (d, 1H), 7.42 (d, 2H), 7.76 (dd,1H), 7.83 (dd, 1H), 8.15 (d, 1H), 8.19 (d, 1H), 8.35 (s, 1H), 8.51 (s,(1H), 9.20 (s, 2H), 9.45 (s, 2H).

EXAMPLE 127F6-[(1,2,3,4-tetrahydro-6-isoquinolinyl)ethynyl]-2-naphthalenecarboximidamide,bis(trifluoroacetate)(salt)

Using the product obtained in Example 127E and the procedure describedin Example 124D, the desired compound was obtained.

MS (ESI) m/z 326 (M+H)⁺; ¹H NMR (300 MHz, DMSO) δ 3.03 (t, 2H), 3.42 (t,2H), 4.35 (s, 2H), 7.35 (d, 1H), 7.46 (d, 2H), 7.78 (dd, 1H), 7.89 (dd,1H), 8.15 (d, 1H), 8.19 (d, 1H), 8.35 (s, 1H), 8.52 (s, 1H), 9.17 (s,2H), 9.31 (s, 2H), 9.48 (s, 2H); Anal. calc'd for C₂₆H₂₁F₆N₃O₄: C,56.42; H, 3.82; N, 7.59. Found: C, 56.31; H, 3.81; N, 7.42.

EXAMPLE 129 5-[[6-(aminoiminomethyl)-2-naphthalenyl]oxy]pentanoic acid,mono(trifluoroacetate)(salt) EXAMPLE 129A

The resulting product from Example 119A (250 mg, 1.477 mmol) was treatedwith methyl 5-bromovalerate in an analogous manner as described inExample 1 19B to yield the desired compound (394 mg, 94%). ^(MS) (DCI(NH₃)) m/z 301 (M+NH₄)⁺.

EXAMPLE 129B 5-[[6-(aminoiminomethyl)-2-naphthalenyl]oxy]pentanoic acid,mono(trifluoroacetate)(salt)

The resulting product from Example 129A (262 mg, 0.8723 mmol) wastreated in an analogous manner as described in Example 94D to yield theester amidine product. The product (140 mg, 0.542 mmol) was dissolved inmethanol (11 mL). To this was added a solution of lithium hydroxide(68.2 mg, 1.626 mmol) in water (3 mL) and the resulting mixture wasstirred at room temperature under an inert atmosphere for 18 hours. Thereaction was evaporated and the residue purified by reverse phasechmomatography to yield the desired compound (184 mg, 74%).

MS (DCI (NH₃)) m/z 287 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆) δ 1.711 (m,2H), 1.817 (m, 2H), 2.320 (t, 2H), 4.144 (t, 2H), 7.377 (dd, 1H), 7.472(d, 1H), 7.632 (dd, 1H), 7.980 (d, 1H), 8.081 (d, 1H), 8.329 (s, 1H),9.100 (br s, 2H), 9.390 (br s, 2H), 12.100 (br s, 1H); Anal. calc'd forC₁₆H₁₈N₂O₃ (C₂HO₂F₃) 1.15.H₂O 0.65: C, 51.22; H, 4.80; N, 6.53. Found:C, 51.30; H, 5.07; N, 6.12.

EXAMPLE 1317-methoxy-8-(3-oxo-1-cyclopenten-1-yl)-2-naphthalenecarboximidamide,mono(trifluoroacetate)(salt) EXAMPLE 131A

The material prepared as described in Example 25A (0.5 g, 1.5 mmol) andthe 3-tributylstannyl-2-cyclopentenone prepared as described by Labourdeet al. Tet Letters 31, (13), 1837-1840 (1990) are coupled via Pdcatalyst as described by the method of Stille et al. JACS 109, 5478-5486(1987) yielding after flash chromatography with 3:1 hexanes/ethylacetate a white solid. 300 mg, 72%.

MS (DCI/NH₃): 281 (M+NH₄).

EXAMPLE 131B7-methoxy-8-(3-oxo-1-cyclopenten-1-yl)-2-naphthalenecarboximidamide,mono(trifluoroacetate)(salt)

The material prepared above (130 mg, 0.4 mmol) is prepared according tothe H₂S/pyridine method described in Example 40D. The desired compoundwas obtained as an off-white solid after reverse phase chromatography.52 mg, 45%.

MS (DCI/NH₃): M+H+281 ¹H NMR (DMSO-d₆): 9.45 (bs, 2H); 9.12 (bs, 2H),8.25-8.32 (m, 2H), 8.20 (dd, 1H), 7.86 (d, 1H), 7.75 (dd, 1H), 6.42 (m,1H), 4.05 (s, 3H), 3.15 (m, 2H), 2.75 (m, 2H); Anal. calc'd forC₁₉H₁₇N₂O₄F₃.1.75 TFA: C, 57.87; H, 4.35; N, 7.10. Found: C, 51.37; H,4.21; N, 7.14.

EXAMPLE 1326-(aminoiminomethyl)-N-(4-methylphenyl)-2-naphthalenecarboxamidemono(trifluoroacetate)(salt) EXAMPLE 132A

p-Toluidine (0.11 g, 1 mmol), and the cyano ester prepared in Example 8E(0.2 g, 1 mmol) are coupled according to the procedure described inExample 8G, providing an off-white solid as the desired compound (0.16g, 56%).

MS (ESI+,−): 287 (M+); 285 (M−).

EXAMPLE 132B6-(aminoiminomethyl)-N-(4-methylphenyl)-2-naphthalenecarboxamide,mono(trifluoroacetate)(salt)

The desired compound is prepared according to the procedure described inExample 6B and purified as described in Example 1B, yielding a whitesolid (35 mg, 35%).

MS (ESI+): 304 (M+) 1HNMR (DMSO-d6): 10.55 (s, 1H); 9.45 (bs, 2H); 9.15(bs, 2H); 8.65 (s, 1H); 8.58 (s, 1H); 8.32 (d, 1H), 8.20 (d, 1H), 8.19(dd, 1H); 7.96 (dd, 1H), 7.75 (d, 2H), 7.12 (d, 2H), 2.35 (s, 3H); Anal.calc'd for C₂₁H₁₈N₃O₃F₃: C, 60.43; H, 4.35; N, 10.07. Found: C, 59.94;H, 4.06; N, 9.80.

EXAMPLE 133 Methyl4-[[[7-(aminoiminomethyl)-1-(2-pyrimidinylamino)-2-naphthalenyl]oxy]methyl]benzoate,mono(trifluoroacetate)(salt) EXAMPLE 133A

The material described in Example 91A is treated with A1l₃ according tothe procedure described in Example 119A and alkylated with4-CarbomethoxyBenzylbromide according to the procedure described inExample 109B, yielding the desired compound as a white solid, 100 mg,83%.

MS (ESI+, −): 411 (M+); 409 (M−).

EXAMPLE 133B Methyl4-[[[7-(aminoiminomethyl)-1-(2-pyrimidinylamino)-2-naphthalenyl]oxy]methyl]benzoate,mono(trifluoroacetate)(salt)

The desired compound is prepared according to the procedure described inExample 40D and purified according to the procedure described in Example119B, yielding a light yellow solid, (49 mg, 50%).

MS (ESI +, −): 428 (M+); 426 (M−) ¹H NMR (DMSO-d6): 9.45 (bs, 2H); 9.15(s, 1H); 8.97 (bs, 2H); 8.45 (dd, 1H); 8.38 (d, 1H); 8.15 (d, 1H), 8.09(d, 1H), 7.95 (d, 2H); 7.76 (d, 1H), 7.68 (dd, 1H), 7.35 (d, 2H), 6.85(d, 2H), 5.39 (s, 2H); 3.85 (s, 3H); Anal. calc'd for C₂₆H₂₂N₅O₅F₃: C,57.67; H, 4.10; N, 12.93. Found: C, 55.34; H, 3.88; N, 12.05.

EXAMPLE 1344-[[[7-(aminoiminomethyl)-1-(2-pyrimidinylamino)-2-naphthalenyl]oxy]medthyl]benzoicacid, mono(trifluoroacetate)(salt)

The material prepared in Example 134 (40 mg) is dissolved in 1:1THF/water. To the clear solution is added LiOH.water (9 mg), theresulting clear solution is stirred 18 hours at room temperature. Thereaction mixture is concentrated to a yellow solid. The solid isdissolved in distilled water, acidified to pH 2 with 3 N HCl and stirred2 hours at room temperature. The desired compound is isolated byfiltration, dried under vacuum as a yellow solid. Yield: 39 mg (46%).

MS (APCI): M+H⁺: 414; ¹H NMR (DMSO-d6): 9.45 (bs, 2H); 9.15 (s, 1H);8.97 (bs, 2H); 8.45 (dd, 1H); 8.38 (d, 1H); 8.15 (d, 1H), 8.09 (d, 1H),7.95 (d, 2H); 7.76 (d, 1H), 7.68 (dd, 1H), 7.35 (d, 2H), 6.85 (d, 2H),5.39 (s, 2H); Anal. calc'd for C₂₅H₂₀N₅O₅F₃Cl.3 H₂O: C, 48.67; H, 4.25;N, 11.35. Found: C, 49.64; H, 4.44; N, 11.69.

EXAMPLE 135 1,1-dimethylethyl[[4-[[[6-(aminoiminomethyl)-2-naphthathalenyl]amino]carbonyl]-phenyl]methyl]carbamate,mono(trifluoroacetate)(salt) EXAMPLE 135A

The material prepared in Example 8B was added to cold (0° C.) sulfuricacid (45 mL). Within 1 minutes at 0° C. bubling started to form. Allowedto bubble at 0° C. for 30 minutes than slowly warmed to roomtemperature. Left at room temperature for 20 minutes, then poured intoice and diluted with water (to approx. 500 mL). The suspension wasplaced in an ice bath and carefully added a solution of 50% aqueoussodium hydroxide so that the temperature would not exceed 35° C. Thelight yellow solid was filtered than washed with water till the washbecame neutral to pH paper (7.0). The product was dried under vacuum.The product was purified on silica gel column using 20% ethyl acetate80%, hexanes as eluent to yield 3.3 g (67%) of light yellow solid.

MS m/z 169 (M+1)⁺.

EXAMPLE 135B

A solution of Example 135A (135 mg, 0.8 mmol),4-N-Boc-aminomethylbenzoic acid (404 mg, 1.6 mmol) and EDCI (307 mg, 1.6mmol) in methylene chloride (25 mL), at room temperature, was added DMAP(3 mg) and stirred overnight. The reaction mixture was diluted withmethylene chloride (60 mL) then washed 2% aqueous hydrochloric acid(2×30 mL), water (20 mL), 0.5 M aqeuos sodium hydroxide (2×50 mL) andbrine. The organic phase was dried over magnesium sulfate andevaporated. The product was purified via on silica column using agradient of 25% to 60% ethyl acetate in hexanes as eluent. Yield 175 mg(54%) of white powder.

EXAMPLE 135C 1,1-dimethylethyl[[4-[[[6-(aminoiminomethyl)-2-naphthalenyl]amino]carbonyl]-phenyl]methyl]carbamate,mono(trifluoroacetate)(salt)

The reaction was carried out in the same manner as described in Example40D. Yield 110 mg (64%).

MS m/z 408 (M+1)⁺ 425 (M+18)⁺; ¹H NMR: 3.30 (s, 9H), 4.22 (d, 2H, J=7.1Hz), 7.42 (d, 2H, J=8.5 Hz), 7.49 (t, 1H, J=7.1 Hz), 7.79 (dd, 1H,J1=8.2 Hz, J2=2.0 Hz), 7.95-8.00 (m, 3H), 8.09 (d, 2H, J=8.45 Hz), 8.42(s, 1H), 8.63 (d, 1H, J=2.0 Hz), 9.18 (br s, 4H), 10.58 (s, 1H); Anal.calc'd for C₂₆H₂₇F₃N₄O₅: C, 58.55; H, 4.85; N, 10.41. Found: C, 58.64;H, 5.11; N, 10.52.

EXAMPLE 136 N-[6-(aminoiminomethyl)-2-naphthalenyl]benzamide,mono(trifluoroacetate)(salt)

The desired compound is prepared as described in Example 135;

¹H NMR (300 MHz, DMSO-d₆) 10.67 (s, 1H), 9.25 (br.s, 4H), 8.65 (d, J=1.5Hz, 1H), 8.43 (d, J=1.4 Hz, 1H), 8.10 (d, J=9.2 Hz, 2H), 8.03-7.97 (m,3H), 7.81-7.78 (m, 1H), 7.65-7.55 (m, 3H). MS (ESI/NH₃) m/z 290 (M+H)⁺;Anal. calc'd for C₁₈H₁₅N₃O.CF₃COOH: C, 59.55; H, 4.00; F, 14.13; N,10.42. Found: C, 50.47; H, 3.88; F, 14.42; N, 10.39.

EXAMPLE 137 1,1-dimethylethyl[[4-[[[6-(aminoiminomethyl)-2-naphathalenyl]amino]carbonyl]-cyclohexyll]methyl]carbamate,mono(trifluoroacetate)(salt) EXAMPLE 137A

To a solution of the 6-Amino-2-naphthalenecarbonitrile prepared inExample 73 (100 mg, 0.6 mmol) in methylene chloride (35 mL) at roomtemperature, was added 1-carboxy-4-(Boc-aminomethyl)cyclohexanes (280mg, 1.1 mmol) followed by 1-ethyl-3-(3-dimethylaminopropyl)carbodiimidehydrochloride (EDAC, 225 mg, 1.2 mmol). After 5 minutes to the reactionmixture was added DMAP (20 mg, catalytic). The reaction was stirred atroom temperature for 72 hours. The reaction mixture was diluted 7:3ethyl acetate: hexanes then filtered through silica gel and washed withthe same solvent mixture.

The organic solvent was washed by aq. Acid (2% Hcl, 2×50 mL), water andaq. Base (10% NaOH, 50 mL). The solvent was dried over magnesium sulfatefiltered and evaporated. Crystalization from ether/hexanes afforded theproduct as white solid. Yield 166 mg (68%).

MS (DCI/NH₃) m/z 408 (M+H)⁺.

EXAMPLE 137B 1,1-dimethylethyl[[4-[[[6-(aminoiminomethyl)-2-naphathalenyl]amino]carbonyl]-cyclohexyll]methyl]carbamate,mono(trifluoroacetate)(salt)

A solution of the substrate (Example 137A) in Pyr: Et₃N (10:1, 20 mL)was bubbled H₂S for 5 minutes. Stirred at room temperature overnight.The reaction mixture was added ethyl acetate (100 mL) followed by 1% aq.KHSO4 (60 mL) and separated; washed organic layer with water (2×50 mL),sodium bicarb. And brine, dried over magnesium sulfate & evaporated. Toa suspension of the resulting solid in acetone (25 mL) and added MeI(1.0 mL). Stirred at 50° C. for 2 hours, all dissolved. Evaporatedsolvent to a complete dryness and added methanol (30 mL) and ammoniumacetate (150 mg). The mixture was stirred at room temperature overnight.Purification by Reverse Phase C₁₈ MPLC. After evaporation added toluene& evaporated (2×40 mL). The resulting oil was treated with methanol andether and the product precipitated as white solid (72 mg, 43%).

MS (ESI/NH₃) m/z 425 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆) 10.24 (s, 1H),9.05 (br.s, 4H), 8.49 (s, 1H), 8.38 (d, J=1.7 Hz, 1H), 8.03-8.00 (m,2H), 7.77-7.74 (m, 2H), 6.93-6.91 (m, 1H), 2.83-2.79 (m, 2H), 2.40-2.30(ml), 1.92-1.75 (m, 4H), 1.50-1.45 (m, 1H), 1.39 (s, 9H), 0.96-0.91 (m,4H); Anal. calc'd for C₂₄H₃₂N₄O₃.CF₃COOH: C, 57.98; H, 6.18; N, 10.40.Found: C, 57.63; H, 6.24; N, 10.21.

EXAMPLE 138N-[6-(aminoiminomethyl)-2-naphthalenyl]-N′-(4-aminophenyl)urea,bis(trifluoroacetate)(salt) EXAMPLE 138A

To a solution of the compound prepared in Example 40B (194.2 mg, 1 mmol)in dioxane (10 mL) at room temperature, was added 4-phenylenediaminemono Boc (416, 5 mg, 2 mmol). The product started to precipitate withinminutes. After an hour the reaction mixture was added ether (5 mL) andthe white solid product was filtered and washed with ether to yield 350mg (87%).

MS (DCI/NH₃) m/z 403 (M+H)⁺.

EXAMPLE 138B

A solution of the corresponding nitrile prepared in Example 138A (105mg, 0.36 mmol) in Pyr: Et₃N (10:1, 20 mL) was bubbled H₂S for 5 minutesand stirred at room temperature overnight. The reaction mixture wasdiluted with ethyl acetate (100 mL) washed with aqueous 0.25 N HCl (25mL) followed by water (2×50 mL), saturated solution of sodiumbicarbonate, and brine, dried over magnesium sulfate & evaporated. To asolution of the resulting solid in acetone (25 mL) was added MeI (1.0mL) and stirred at 50° C. for 30 minutes—very strong precipitate wasobserved. Added ether and filtered the yellow precipitated. The yellowsolid was added methanol (10 mL) and ammonium acetate (150 mg) andstirred at room temperature overnight. Purified as described in Example1B. Yield of the white solid 69 mg.

MS (DCI/NH₃) m/z 420 (M+H)⁺.

EXAMPLE 138CN-[6-(aminoiminomethyl)-2-naphthalenyl]-N′-(4-aminophenyl)urea,bis(trifluoroacetate)(salt)

The Boc protected substrate (Example 138B) was dissolved in methylenechloride: TFA 1:1 (25 mL) and stirred at room temperature for 1 hour.Evaporated solvent under vacuum added toluene & evaporated again. Addedwater & little acetonitrile, filtered & lyophilized. 36 mg of whitesolid.

MS (ESI/NH₃) m/z 320 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆) 9.26 (br.s, 2H),9.21 (br.s, 1H), 8.85 (br.s, 2H), 8.31 (d, J=1.7 Hz, 1H), 8.18 (d, J=1.7Hz, 1H), 7.95-7.91 (m, 2H), 7.68 (dd, J1=6.6 Hz, J2=2.0 Hz, 1H), 7.57(dd, J1=9.2 Hz, J2=1.4 Hz, 1H), 7.34 (d, J=8.8 Hz, 2H), 6.91 (d, J=8.4Hz, 2H); Anal. calc'd for C₁₈H₁₇N₅O.2.CF₃COOH.H₂O: C, 46.73; H, 3.74; N,12.39. Found: C, C, 47.03; H, 3.55; N, 12.36.

EXAMPLE 139N-[6-(aminoiminomethyl)-2-naphthalenyl]-4-4-(aminomethyl)cyclohexanescarboxamide,bis(trifluoroacetate)(salt)

A solution of the substrate prepared in Example 137 as TFA salt (45 mg)in methylene chloride: TFA 1:1 (20 mL) was stirred at room temperaturefor 1 hour. The solvent was evaporated under vacuum, added toluene &evaporated (20 mL×2). Dissolved in water, filtered—0.45 μ frit andlyophilized. 35 mg, white solid as bis TFA salt.

MS (ESI/NH₃) m/z 325 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆) 10.31 (s, 1H),9.31 (br.s, 2H), 9.10 (br.s, 2H), 8.49 (s, 1H), 8.39 (s, 1H), 8.04-8.00(m, 2H), 7.78-7.71 (m, 2H), 2.71 (d, J=7.0 Hz, 2H), 2.44-2.36 (m, 1H)1.96-1.85 (m, 4H), 1.61-1.42 (m, 3H), 1.09-1.02 (m, 2H); Anal. calc'dfor C₁₉H₂₄N₄O.2.CF₃COOH: C, 50.00; H, 4.74; N, 10.14. Found: C, 49.95;H, 4.70; N, 09.96.

EXAMPLE 140N-[6-(aminoiminomethyl)-2-naphthalenyl]-N′-[(4-aminomethyl)phenyl]urea,bis(trifluoroacetate)(salt) EXAMPLE 140A

To a solution of the isocyanate prepared in Example 40B (140 mg, 0.72mmol) in dioxane (8.0 mL) at room temperature, was added4-N-Boc-aminomethylbenzoic acid (320 mg, 1.44 mmol) and stirred for 1hour. The product was precipitating during the reaction. The mixturediluted with ether (15 mL), filtered and washed with ether to yield 215mg (72%) of white solid.

MS (DCI/NH₃) m/z 417 (M+H)⁺.

EXAMPLE 140B

A solution of the nitrile (Example 140A) (198 mg, 0.47 mmol) in 10:1pyridine: trimethylamine (10 mL) was treated with H₂S for 5 min, stirredat room temperature for 18 h and concentrated. The resulting solid wasdissolved in acetone (15 mL), treated with iodomethane (0.8 mL, 12.8mmol), stirred for 2 hours, diluted with ether (10 mL), filtered, washedwith ether and dried under vacuum. The resulting solid was dissolved inmethanol (4 mL) and was added NH₄OAc (200 mg, 2.6 mmol) at roomtemperature overnight. The product was purified according to theprocedure described in Example 1B to provide 112 mg (54%) of thecorresponding amidine.

MS (DCI/NH₃) m/z 434 (M+H)⁺.

EXAMPLE 140CN-[6-(aminoiminomethyl)-2-naphthalenyl]-N′-[(4-aminomethyl)phenyl]urea,bis(trifluoroacetate)(salt)

A solution of the substrate (Example 140B) in methylene chloride: TFA1:1 (20 mL) was stirred at room temperature for 1 hour. The solvent wasevaporated under vacuum, added toluene & evaporated (20 mL×2). Dissolvedin water, filtered—0.45 μ frit and lyophilized. 38.1 mg, white solid.

MS (ESI/NH₃) m/z 334 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆) 9.68 (s, 1H),9.45 (s, 1H), 9.35 (br.s, 2H), 9.08 (br. s, 2H), 8.40 (d, J=1.7 Hz, 1H),8.31 (d, J=1.8 Hz, 1H), 8.10 (br.s, 3H), 8.04-7.99 (m, 2H), 7.76 (dd,J1=8.8 Hz, J2=1.8 Hz, 1H), 7.67 (dd, J1=8.8 Hz, J2=1.7 Hz, 1H), 7.58 (d,J=8.4 Hz, 2H), 7.39 (d, J=8.4 Hz, 2H), 3.98 (br. s, 2H); Anal. calc'dfor C₁₉H₁₉N₅O₁.2.CF₃COOH.H₂O: C, 47.67; H, 4.00; F, 19.67; N, 12.09.Found: C, 47.33; H, 3.70; F, 19.59; N, 11.71.

EXAMPLE 141 Methyl[7-(aminoiminomethyl)-3-[[[4-(aminomethyl)phenyl]amino]carbonyl]-1-naphthalenyl]carbamate,bis(trifluoroacetate)(salt) EXAMPLE 141A

To a solution of the ester, prepared as described in Example 26, (747mg, 2.63 mmol) in dioxane (10 mL) was added acetone (1 mL) and an excessof sodium hydroxide (1 N in water, 10 mL). After 1 hour the mixture wasadded water (40 mL) and ethyl acetate (85 mL) then was acidified with10% aq. HCl. The ethyl acetate layer was separated washed with water(2×20 mL) then brine, dried over magnesium sulfate filtered andevaporated. The product was isolated as a light yellow solid.

MS m/z 271 (M+I)⁺.

EXAMPLE 141B

To a suspension of naphthoic acid derivative, prepared in Example 141A(270 mg, 1.1 mmol) in methylene chloride (8.0 mL) was addeddiisopropylethylamine (DIEA, 485μL, 2.8 mmol) followed byO-(azabenzotriazole-1-yl)-N, N, N′,N′-tetramethyluroniumhexafluorophosphate (HATU, 527 mg, 1.39 mmol).After 10 minutes added the 4-N-Boc-aminomethylaniline (370 mg, 1.7mmol). After an hour, added ethyl acetate (120 mL) and washed organiclayer with 5% aq. citric acid (50 mL), water (2×40 mL) and brine (50mL). The rxn was dried over magnesium sulfate filtered through smallamount of silica and evaporated. Purification on silica eluting withethyl acetate in hexanes. The product, after concentration, was addedethyl acetate and ether and filtered to yield 350.0 mg (70%) of yellowsolid.

MS m/z 447 (M+1)⁺.

EXAMPLE 141C

A suspension of the naph derivative (Example 141B) (300 mg, 0.67 mmol)in ethyl acetate (20 mL) was added 120(mg of the Pd catalyst thenstirred at room temperature, under hydrogen, at atmospheric pressure andstirred for 1 hour. The crude was carried on to the next step withoutany purifications or analysis.

To a solution of the crude amine in dioxane (25 mL) and 10% aqeuossodium carbonate (2.5 mL) was added the methyl chloroformate (1.0 mL,large excess). After 2 hours the rxn was quenched with methanol thendiluted with ethyl acetate (80 mL) and water (50 mL). The ethyl acetatelayer was separated, dried over magnesium sulfate filtered andevaporated. The product was separated on silica column using a gradientof ethyl acetate in hexanes (from 5 to 30% ethyl acetate in hexanes).Yield 140 mg of off white solid.

MS m/z 492 (M+18)⁺.

EXAMPLE 141D

The desired compound was prepared as described in Example 26.

MS m/z 492 (M+1⁺.

EXAMPLE 141E Methyl[7-(aminoiminomethyl)-3-[[[4-(aminomethyl)phenyl]aminoicarbonyl]-1-naphthalenylcarbamate, bis(trifluoroacetate)(salt)

A solution of the substrate (Example 141D) in a mixture of methylenechloride: TFA 4:1 (20 mL) was stirred at room temperature for 15minutes. The solvent was concentrated under vacuum, and separated on RPC18 MPLC. Yield, 21 mg off white solid.

MS m/z 392 (M+18)⁺; ¹H NMR (DMSO): 3.783 (s, 3H), 4.03 (q, 2H, J=5.5Hz), 7.47 (d, 2H, j=8.4 Hz), 7.85 (d, 2H, j=8.4 Hz), 7.94 (d, 1H, j=8.8Hz), 8.15 (wide s, 2H), 8.31 (d, 1H, j=8.8 Hz), 8.33 (s, 1H), 8.47 (s,1H), 8.74 (s, 1H), 9.29 (s, 2H), 9.47 (s, 2H), 9.90 (s, 1H), 10.68 (s,1H). Anal. calc'd for C₂₅H₂₅F₆N₅O₈ (base molecule+2 TFA+1 H₂O): C,47.04; H, 3.70; N, 10.52. Found: C, 47.10; H, 3.95; N, 10.99.

EXAMPLE 1426-(aminoiminomethyl)-N-(4-ethylphenyl)-2-naphthalenecarboxamide,acetate(salt) EXAMPLE 142A

The reaction was carried out in the same manner as described in Example141B. Yield 374 mg (61%) of white powder.

MS DCI/NH₃): m/z 301 (M+NH₄+).

EXAMPLE 142B6-(aminoiminomethyl)-N-(4-ethylphenyl)-2-naphthalenecarboxamide,acetate(salt)

The reaction was carried out in the same manner as described for thenaphthyl analog prepared in Example 141D, 313 mg. The solid thatprecipitated during the last step was filtered and washed in ether toyield 71 mg (18%) of white solid, as acetate salt.

MS (ECI) m/z 301 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆) δ 1.19 (t, J=7.4 Hz,3H), 2.60 (q, J=7.4 Hz, 2H), 7.22 (d, J=8.5 Hz, 2H), 7.72 (d, J=8.5 Hz,2H), 7.94 (dd, J₁=8.8 Hz, J₂=1.7 Hz, 1H), 8.08-8.23 (m, 3H), 8.47 (d,J=1.7 Hz, 1H), 8.63 (s, 1H), 10.43 (br. s, 1H); Anal. calc'd forC₂₀H₁₉N₃O.AcOH.0.5 H₂O: C, 68.38; H, 6.26; N, 10.87. Found: C, 68.56; H,6.21; N, 10.67.

EXAMPLE 1436-(aminoiminomethyl)-N-(2-naphthalenyl)-2-naphthalenecarboxamide,mono(trifluoroacetate)(salt) EXAMPLE 143A

To a solution of the acid chloride prepared as described in Example 8B(341 mg, 1.6 mmol) in methylene chloride (20 mL) was added a solution ofthe 2-Amino naphthalene (249 mg, 1.74 mmol) in methylene chloride (10mL) and propylene oxide (12 mL). The rxn was stirred at room temperatureovernight. The reaction mixture was added ether and the product wasfiltered, washed with ether and hexanes and dried under vacuum. Yield440 mg (86%).

MS (DCI/NH3) m/z 340 (M+NH4)⁺.

EXAMPLE 143B6-(aminoiminomethyl)-N-(2-naphthalenyl)-2-naphthalenecarboxamide,mono(trifluoroacetate)(salt)

The desired compound is prepared as described in Example 141B. Yield ofwhite solid 40 mg (10%).

MS (ESI) m/z 340 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆) 7.43-7.55 (m, 2H),7.86-7.96 (m, 5H), 8.20-8.28 (m, 2H), 8.08-8.23 (m, 3H), 8.34 (d, J=8.8Hz, 1H), 8.50 (d, J=1.7 Hz, 1H), 8.57 (d, J=1.3 Hz, 1H), 8.75 (s, 1H),9.33 (br. s, 4H) 10.75 (s, 1H); Anal. calc'd for C₂₂H₁₇N₃O.TFA.0.25 H₂O:C, 62.95; H, 4.07; N, 9.18. Found: C, 63.09; H, 3.72; N, 8.99.

EXAMPLE 144 6-(5-phenyl-2-oxazolyl)-2-naphthalenecarboximidamide,mono(trifluoroacetate)(salt) EXAMPLE 144A

To a suspension of the phenacyl amine hydrochloride (Aldrich) (415 mg,2.42 mmol) in a mixture of methylene chloride (50 mL) and propyleneoxide (15 mL) at room temperature was added a solution of the2-nitrile-6-acidchloride (560 mg, 2.6 mmol) in methylene chloride (30mL) followed by DMF (3.0 mL). The reaction was stirred at roomtemperature overnight. The reaction mixture was added ether (15 mL) andthe product was filtered and washed with hexanes to yield 555 mg (73%)of white solid.

MS (DCI/NH₃) m/z 315 (M+H)⁺.

EXAMPLE 144B

A suspension of the substrate (Example 144A) (354 mg, 1.12 mmol) inphosphorous oxychloride (3.5 mL) was boiled for 1.5 hours. The reactionmixture was poured into ice and the mixture was added ethyl acetate (80mL) and aqeuous solution of 10% potassium carbonate (100 mL). Theorganic layer was separated, washed with brine dried over magnesiumsulfate and evaporated. Added ether and filtered 249 mg (75%).

MS (DCI/NH₃) m/z 297 (M+H)⁺.

EXAMPLE 144C 6-(5-phenyl-2-oxazonyl)-2-naphthalenecarboximidamide,mono(trifluoroacetate)(salt)

To a solution of the substrate Example 144B (132 mg, 0.44 mmol) in THF(20 mL) at room temperature was added a solution of 1 N LiHMDS inhexanes (1.5 mL, 1.5 mmol) and stirred overnight. Quenched with 4 N HClin dioxane (1 mL). After 10 minutes added a few drops of water andstirred for additional 30 minutes. The solvent was evaporated undervacuum and the residue was purified on reverse phase chromatography.Yield 58 mg of white solid 41%).

MS (ESI/NH₃) n/z 314 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆) 9.50 (s, 2H),9.19 (s, 2H), 8.86 (s, 1H), 8.55 (s, 1H), 8.38-8.26 (m, 3H), 7.98 (s,1H), 7.96-7.89 (m, 3H), 7.58-7.54 (m, 2H), 7.47-7.42 (m, 1H); Anal.calc'd for C₂₀H₁₅N₃O.1.15CF₃COOH: C, 60.26; H, 3.66; N, 9.45; F, 14.75.Found: C, 60.11; H, 3.81; N, 9.20; F, 14.81.

EXAMPLE 145 6-(5-phenyl-2-thiazolyl)-2-naphthalenecarboximidamide,mono(trifluoroacetate)(salt) EXAMPLE 145A

A suspension of the substrate, prepared in Example 144A, (340 mg, 1.1mmol) and Lawesson's reagent (600 mg, 1.48 mmol) was heated to 85° C.for 48 hours. Solvent was evaporated to dryness and the product wasisolated via silica column using 10% ethyl acetate in hexanes as eluent.Yield: 200.0 mg (59%) of yellow solid.

MS (DCI/NH₃) m/z 313 (M+H)⁺.

EXAMPLE 145B 6-(5-phenyl-2-thiazolyl)-2-naphthalenecarboximidamide,mono(trifluoroacetate)(salt)

To a solution of the substrate, Example 145A (180 mg, 0.58 mmol) in THF(20 mL) at room temperature was added a solution of 1 N LiHMDS inhexanes (2.0 mL, 2.0 mmol) and stirred overnight. Quenched with 4 N HClin dioxane (1 mL). After 10 minutes added a few drops of water andstirred for additional 30 minutes. The solvent was evaporated undervacuum and the residue was purified on MPLC RPC18. Yield 36 mg (19%) ofwhite solid.

MS (ESI/NH₃) m/z 330 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆) 9.49 (s, 2H),9.14 (s, 2H), 8.71 (s, 1H), 8.52 (s, 1H), 8.47 (s, 1H), 8.35-8.22 (m,3H), 7.90-7.78 (m, 3H), 7.55-7.50 (m, 2H), 7.46-7.43 (m, 1H); Anal.calc'd for C₂₀H₁₅N₃S.CF₃COOH.H₂O: C, 57.26; H, 3.93; N, 9.11. Found: C,56.83; H, 3.55; N, 8.79.

EXAMPLE 1466-(aminoiminomethyl)-4-(3-furanyl)-N-(2-pyridinyl)-2-naphthalenecarboxamide,dihydrochloride EXAMPLE 146A

The above product was prepared in the manner of Example 114A.

MS (ESI) m/z (M+H)⁺ 340.

EXAMPLE 146B6-(aminoiminomethyl)-4-(3-furanyl)-N-(2-pyridinyl)-2-naphthalenecarboxamide,dihydrochloride

The above was prepared from Example 146A using method described in 145B.

MS (CI) m/z (M+H)⁺ 357; ¹H-NMR (300 MHz, DMSO-d₆) δ 11.27 (s, 1H), 9.56(s, 2H), 9.17 (s, 2H), 8.76 (s, 1H), 8.63 (s, 1H), 8.45-8.24 (m, 5H),7.96-7.89 (m, 3H), 7.25 (m, 2H), 7.18 (s, 1H); Anal. calc'd forC₂₁H₁₈N₄O₂Cl₂ 19/10 HCl: C, 54.33 H, 4.75 N, 12.07. Found: C, 54.89; H,5.28; N, 9.81.

EXAMPLE 1476-(aminoiminomethyl)-N-(1,2,3,4-tetrahydro-6-quinolinyl)-2-naphthalenecarboxamide,bis(trifluoroacetate)(salt) EXAMPLE 147A

The reaction was carried out in exactly the same manner as described forExample 118A using 6-aminoquinoline to yield the product in 72%. Massspectrum (CI+) 324 (M+1)⁺.

EXAMPLE 147B

The reaction was carried out in exactly the same manner as described forExample 118B to yield the product in 45% (off white solid). Massspectrum (ESI+) 341 (M+1)⁺.

EXAMPLE 147C6-(aminoiminomethyl)-N-(1,2,3,4-tetrahydro-6-quinolinyl)-2-naphthalenecarboxamide,bis(trifluoroacetate)(salt)

To a suspension of the substrate, Example 147B (261 mg, 0.6 mmol) indegassed methanol (15 mL) was added platinum oxide (10 mg, cat.). Thereaction mixture was charged with hydrogen at atmospheric pressure andstirred vigorously overnight. The next day the solution was filteredthrough celite to remove the catalyst, and the product was purified overmplc with RPC18 silica using methanol (+0.1% (TFA) and water (+0.1% TFA)as eluent. Yield 122 mg of white solid and bis TFA salt.

MS (ESI+) 345 (M+1)⁺; ¹H NMR (DMSO-d₆) 10.51 (s, 1H), 9.65 (s, 2H), 9.50(s, 2H), 8.64 (s, 1H), 8.52 (s, 1H), 8.22 (d, J=8.0 Hz, 1H), 8.12 (Abq,J=9.0 Hz, 2H), 7.86 (d, J=9.0 Hz, 1H), 7.61 (s, 1H), 7.56 (d, J=8.0 Hz,1H), 6.98 (d, J=8.5 Hz, 1H), 3.28 (t, J=5.5 Hz, 2H), 2.75 (t, J=6.3 Hz,2H), 1.92-1.86 (m, 2H); Anal. calc'd for C₂₁H₂ON₄O+2.25 TFA+0.25 H₂O: C,50.59 (50.46); H, 3.79; N, 9.25 (9.25); F, 21.18 (20.83).

EXAMPLE 148 7-methoxy-8-(pyrazinyloxy)-2-naphthalenecarboximidamide,dimethanesulfonate(salt) EXAMPLE 148A

The product from Example 4A (125 mg, 0.627 mmol) was combined withchloropyrazine (112 mL, 1.25 mmol) and Cs₂CO₃ (409 mg, 1.25 mmol) inN-methylpyrrolidinone (4 mL), and the reaction was stirred at 130° C.for 1 hour. The reaction was cooled, and the crude mixture waschromatographed on SiO₂ using 40% ethyl acetate/hexanes as eluent, toyield 75 mg (43%) of the desired compound.

MS (DCI (NH₃) m/z 278 (M+H)⁺.

EXAMPLE 148B 7-methoxy-8-(pyrazinyloxy)-2-naphthalenecarboximidamide,dimethanesulfonate(salt)

The product from Example 148A (70 mg, 0.252 mmol) was subjected to theprocedure described in Example 1B to yield the desired compound (106 mg,71%) m.p. 155° C.

MS (DCI (NH₃) m/z 295 (M+H)⁺; ¹H NMR (300 MHz, DMSO) δ 9.42 (br s, 2H),9.04 (br s, 2H), 8.72 (s, 1H), 8.38 (d, J=3 Hz, 1H), 8.36 (m, 1H), 8.21(d, J=9 Hz, 1H), 8.09 (m, 1H), 8.06 (d, J=9 Hz, 1H), 7.82 (d, J=9 Hz,1H), 7.73 (dd, J=9, 2 Hz, 1H), 3.83 (s, 3H), 2.38 (s, 3H); Anal. calc'dfor C₁₈H₂₂N₄S₂O₈.1.1CH₄SO₃: C, 38.74; H, 4.49; N, 9.46. Found: C, 36.68;H, 4.53; N, 9.34.

EXAMPLE 149 7-methoxy-8-(phenylthio)-2-naphthalenecarboximidamide,methanesulfonate EXAMPLE 149A

To a solution of NaH (48 mg, 60%, 1.2 mmol) in HMPA (2 mL) was addedPhSH (0.133 mL, 1.3 mmol), and the reaction was stirred for 5 minutes.To this was added the product from Example 53B (309 mg, 1 mmol), and thereaction was heated at 100° C. for 3 hours. The crude reaction mixturewas chromatographed on SiO₂ using 20% ethyl acetate/hexanes as eluent.The product was taken up in ethyl acetate (10 mL) and methanol (10 mL),and treated with a 2 M solution of TMSCHN₂ (10 mL). The reaction wasstirred for 60 minutes and condensed. The crude product waschromatographed on SiO₂ using 15% ethyl acetate/hexanes as eluent, toyield 115 mg (39%) of the desired compound:

MS (DCI (NH₃) m/z 309 (M+NH₄)⁺.

EXAMPLE 149B 7-methoxy-8-(phenylthio)-2-naphthalenecarboximidamide,methanesulfonate

The desired compound was prepared from Example 149A and the procedure ofExample 55D.

MS (DCI/NH₃) m/z 309 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆) δ 2.33 (s, 3H),3.96 (s, 3H), 6.96 (d, 2H), 7.11 (dd, 1H), 7.20 (d, 1H), 7.22 (d, 1H),7.69 (dd, 1H), 7.82 (d, 1H), 8.22 (d, 1H), 8.33 (d, 1H), 8.81 (s, 1H),9.01 (br s, 2H), 9.46 (br s, 2H); Anal. calc'd for C₁₈H₁₆N₂OS.1.15CH₄SO₃: C, 54.91; H, 4.96; N, 6.69. Found: C, 54.70; H, 5.15; N, 6.58.

EXAMPLE 150 7-methoxy-8-(pyrazinylamino)-2-naphthalenecarboximidamide,bis(trifluoroacetate)(salt)

The desired compound was prepared from the product prepared in Example90D using the method described in Example 91A, then converted to theamidine as described in Example 40D.

MS (DCI/NH₃) m/z (M+H)⁺ 294; ¹H-NMR (300 MHz, DMSO-d₆) δ 9.39 (s, 2H),9.02 (s, 2H), 8.95 (s, 1H), 8.40 (d, 1H), 8.14 (d, 1H), 8.03 (s, 2H),7.92 (dd, 1H), 7.84 (d, 1H), 7.76 (d, 1H) 7.66 (dd 1H), 3.90 (s, 3H);Anal. calc'd for C₂₀H₁₇N₅O₅F₆ ½TFA: C, 43.79; H, 3.07; N, 12.20. Found:C; 43.81; H, 3.22; N, 12.24.

EXAMPLE 1526-(aminoiminomethyl)-4-(3-furanyl)-N-phenyl-2-naphthalenecarboxamide,monohydrochloride EXAMPLE 152A

To a solution of the product from Example 8D (5.50 g, 26.04 mmol) inCH₂Cl₂ (125 mL) was added dibromodimethylhydantoin (4.47 g, 15.62 mmol)and trifluoromethanesulfonic acid (2.51 mL, 28.41 mmol), and thereaction was stirred at 23° C. in the dark for 18 hours. The mixture waspoured into aqueous NaHSO₃, the solution was made basic with Na₂CO₃, andextracted with 3× ethyl acetate, and the extracts were washed withbrine, dried over Na₂SO₄, and condensed. The product was recrystallizedfrom ethanol/ethyl acetate, to yield 5.80 g (77%) of the desiredcompound.

MS (DCI (NH₃) m/z 307 (M+NH₄)⁺.

EXAMPLE 152B

To a solution of the product from Example 152A (1.40 g, 4.826 mmol) inTHF (40 mL), water (10 mL), and methanol (10 mL) was added LiOH water(405 mg, 9.65 mmol), and the reaction was stirred for 18 hours. Themixture was poured into 1 M HCl and extracted with 3× ethyl acetate, andthe extracts were washed with brine, dried over Na₂SO₄, and condensed,to yield 1.23 g (92%) of the desired compound.

MS (DCI (NH₃)) m/z 295 (M+NH₄)⁺.

EXAMPLE 152C

To a solution of the product from Example 152B (440 mg, 1.60 mmol), intoluene (25 mL) was added oxanyl chloride (0.140 mL, 1.6 mmol), and thereaction was stirred at 80° C. for 18 hours. The toluene was boiled offuntil HCl evolution ceased, and the reaction was then cooled. Aniline (1mL, 11 mmol) was added, and the reaction was stirred for 10 min, nadpoured into 1 M HCl. The solution was extracted with 3× ethyl acetate,and the extracts were washed with brine, dried over Na₂SO₄, andcondensed, to yield 560 mg (99%) of the desired compound.

MS (DCI (NH₃)) m/z 370 (M+NH₄)⁺.

EXAMPLE 152D

The desired compound was prepared from Example 152C (408 mg, 1.16 mmol),furan-3-boronic acid (182 mg, 1.62 mmol) and the procedure of Example57B, to yield 220 mg (56%) of the desired compound.

MS (DCI (NH₃)) m/z 356 (M+NH₄)⁺.

EXAMPLE 152E6-(aminoiminomethyl)-4-(3-furanyl)-N-phenyl-2-naphthalenecarboxamide,monohydrochloride

The desired compound was prepared from Example 152D and the procedure ofExample 40D.

MS (DCI/NH₃) m/z 356 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆) δ 7.15 (m, 2H),7.41 (dd, 2H), 7.83 (d, 2H), 7.91 (d, 1H), 7.99 (dd, 1H), 8.19 (d, 1H),8.38 (s, 1H), 8.41 (d, 1H), 8.62 (s, 1H), 8.69 (s, 1H), 9.15 (br s, 2H),9.55 (br s, 2H); Anal. calc'd for C₂₂H₁₇N₃O₂.2.75 HCl: C, 57.99; H,4.37; N, 9.22. Found: C, 57.85; H, 4.84; N, 9.44.

EXAMPLE 1536-(aminoiminomethyl)-4-[1-(methylsulfonyl)-1H-pyrazol-4-yl]-N-phenyl-2-naphthalenecarboxamide,monohydrochloride EXAMPLE 153A

The desired compound was prepared from the product from Example 53D andthe product from Example 152A by the procedure of Example 47A.

MS (DCI/NH₃) m/z 408 (M+H)⁺.

EXAMPLE 153B

The desired compound was prepared from the product from Example 153A, bythe procedure of Example 53F.

MS (DCI/NH₃) m/z 278 (M+H)⁺.

EXAMPLE 153C

The desired compound was prepared from the product from Example 153B, bythe procedure of Example 87A (86A).

MS (DCI/NH₃) m/z 373 (M+NH₄)⁺.

EXAMPLE 153D

The desired compound was prepared from the product from Example 153C, bythe procedures of Example s 152B and 152C

MS (DCI/NH₃) m/z 356 (M−SO₂Me+NH₄)⁺.

EXAMPLE 153E6-(aminoiminomethyl)-4-[1-(methylsulfonyl)-1H-pyrazol-4-yl]-N-phenyl-2-naphthalenecarboxamide,monohydrochloride

The desired compound was prepared from Example 153D and the procedure ofExample 40D.

MS (DCI/NH₃) NONE; ¹H NMR (300 MHz, DMSO-d₆) δ 3.99 (s, 3H), 7.14 (t,1H), 7.40 (t, 2H), 7.84 (d, 2H), 7.91 (d, 1H), 8.08 (s, 1H), 8.15 (d,1H), 8.35 (m, 2H), 8.65 (br s, 2H), 9.33 (br s, 2H), 9.61 (br s, 2H),10.58 (s, 1H); Anal. calc'd for C₂₂H₁₉N₅SO₃2.75 HCl: C, 49.51; H, 4.11;N, 13.12. Found: C, 49.44; H, 3.83; N, 12.09.

EXAMPLE 1546-(aminoiminomethyl)-4-[5-(methylthio)-3-furanyl)]-N-phenyl-2-naphthalenecarboxamide,monohydrochloride EXAMPLE 154A

To a solution of 2-trimethylsilyl-3-bromofuran (4.17 g, 19.03 mmol) inTHF (40 mL) at −78° C. was added a 1.5 M solution of LDA (12.7 mL, 19.03mmol), and the reaction was stirred at −78° C. for 1 hour. Methyldisulfide (1.89 mL, 20.93 mmol) was then added, and the reaction wasallowed to warm to room temperature overnight. The reaction was pouredinto saturated aqueous NH₄Cl solution, and extracted with 3× dimethylether. The combined extracts were washed with brine, dried over Na₂SO₄,and condensed. The crude material was chromatographed on SiO₂ usinghexanes as eluent, to yield 3.02 g (60)%) of the desired compound.

MS (DCI/NH₃) m/z 265, 267 (M+H)⁺.

EXAMPLE 154B

A solution of the product from Example 154A (2.68 g, 10.1 mmol) and a 1M solution of TBAF (20.2 mL) in THF (20 mL) was stirred for 30 minutes.The reaction was condensed and The desired compound was chromatographedon SiO₂ using hexanes as eluent, to yield 1.39 g (71%) of2-methylthio-4-bromofuran. This material was taken on directly to thenext step. To a solution of this product (7 mmol) in THF (25 mL) at −78°C. was added a 2.5 M solution of BuLi (2.8 mL, 7 mmol), and the reactionwas stirred for 5 minutes. Bu₃SnCl (1.90 mL, 7 mmol) was then added, thereaction was stirred for 30 min, and then allowed to warm to roomtemperature. The reaction was poured into saturated aqueous NH₄Clsolution, and extracted with 3× dimethyl ether. The combined extractswere washed with brine, dried over Na₂SO₄, and condensed. The crudematerial was chrormatographed on SiO₂ using hexanes as eluent, to yield1.24 g (30%) of the desired compound.

MS (DCI/NH₃) m/z 404 (M+H)⁺.

EXAMPLE 154C

A solution of the product from Example 154B (920 mg, 2.28 mmol), theproduct from Example 152A (662 mg, 2.28 mmol), and PdCl₂ (PPh₃)₂ (161mg, 0.23 mmol) in CH₃CN (15 mL) was stirred for 18 hours at 80° C. Thereaction was condensed and the crude material was chromatographed onSiO₂ using 20% ethyl acetate/hexanes as eluent, to yield 671 mg (91%) ofthe desired compound.

MS (DCI/NH₃) m/z 324 (M+H)⁺.

EXAMPLE 154D

The desired compound was prepared from the product from Example 154C, bythe procedure of Example 152B.

MS (DCI/NH₃) m/z 310 (M+H)⁺.

EXAMPLE 154E

The desired compound was prepared from the product from Example 154D, bythe procedure of Example 152C.

MS (DCI/NH₃) m/z 402 (M+NH₄)⁺.

EXAMPLE 154F6-(aminoiminomethyl)-4-[5-(methylthio)-3-furanyl)]-N-phenyl-2-naphthalenecarboxamide,monohydrochloride

The desired compound was prepared from Example 154E and the procedure ofExample 144C.

MS (DCI/NH₃) m/z 402 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆) δ 2.54 (s, 3H),7.15 (t, 1H), 7.24 (s, 1H), 7.40 (t, 2H), 7.84 (d, 2H), 7.92 (dd, 1H),8.19 (d, 1H), 8.39 (d, 1H), 8.44 (s, 1H), 8.61 (s, 1H), 8.69 (s, 1H),9.35 (br s, 4H), 10.61 (s, 1H); Anal. calc'd for C₂₃H₁₉N₃SO₂.2.25 HCl:C, 57.14; H, 4.43; N, 8.69. Found: C, 57.13; H, 4.21; N, 8.56.

EXAMPLE 155 Methyl [7-(aminoiminomethyl)-1-naphthalenyl]methylcarbamate,mono(trifluoroacetate) (salt)

The desired compound is prepared according to the procedures describedin Examples 12 and 13. Yield: 40 mg (42%) of white solid

MS m/z: 258 (M+H)⁺; ¹H NMR (DMSO, 300 MHz): 3.28 (s, 3H), 3.82 (br, 3H),7.66 (dd, 1 H, J1=7.5 Hz, J2=1.4 Hz), 7.78 (m, 1H), 8.89 (Dd, 1H, J1=8.8Hz, J2=2.0 Hz), 8.05 (d, 1H, 8.1 Hz), 8.24 (d, 1H, 8.8 Hz), 8.30 (s,1H), 9.09 (s, 2H), 9.52 (s, 2H); Anal. calc'd for C₁₄H₁₅N₃O₂.1.25C₂F₃O₂H.0.25 H₂O: C, 49.02; H, 4.18; N, 10.39. Found: C, 48.81; H, 3.91;N, 10.15.

EXAMPLE 156 propyl [7-(aminoiminomethyl)-1-naphthalenyl]carbamate,mono(trifluoroacetate)(salt)

The desired compound is prepared according to the procedures describedin Examples 12 and 13. Yield: 52 mg (46%) of white solid

MS m/z: 272 (M+H)⁺ ¹H NMR (DMSO, 300 MHz): 0.97 (t, 3H, J1=J2=7.1 Hz),1.67 (Sextet, 2H, J=7.1 Hz), 4.19 (t, 3H, J1=J2=6.8 Hz). 7.71 (d, 1H,8.5 Hz), 7.83 (m, 3H), 8.14 (d, 1H, J=8.5 Hz), 8.67 (s, 1H), 9.22 (Br,3H), 9.63 (s, 1H); Anal. calc'd for C₁₅H₁₇N₃O₂.0.25 C₂F₃O₂H.0.75 H₂O: C,49.18; H, 4.66; N, 9.83. Found: C, 49.27; H, 4.87; N, 10.02.

EXAMPLE 157 N-[7-(aminoiminomethyl)-1-naphthalenyl]-N′-methylurea,mono(trifluoroacetate)(salt)

The desired compound is prepared according to the procedures describedin Examples 12 and 13. Yield: 36 mg (547,) of white solid

MS m/z: 243 (M+H)⁺ ¹H NMR (DMSO, 300 MHz): 2.80 (d, 1H), 6.45 (d, 1H),7.70 (m, 2H), 7.82 (dd, J1=8.9 Hz, J2=2.1 Hz), 8.08 (dd, 7.4 Hz, J=1.3Hz), 8.17 (d, 1H, J=8.5 Hz), 8.62 (s, 1H), 8.72 (s, 1H), 9.07 (s, 2H),9.47 (s, 2H), (s, 2H); Anal. calc'd for C₁₃H₁₄N₄O.1.5 C₂F₃O₂H.0.5 H₂O:C, 45.50; H, 3.94; N, 13.27. Found C, 45.22; H, 3.86; N, 13.12.

EXAMPLE 158 Ethyl [7-(aminoiminomethyl)-1-naphthalenyl)carbamate,mono(trifluoroacetate)(salt)

The desired compound is prepared according to the procedures describedin Examples 12 and 13. Yield: 70 mg (76%) of white solid

MS m/z: 258 (M+H)⁺ ¹H NMR (DMSO, 300 MHz): 1.30 (t, 3H, J1=J2=7.4 Hz),4.20 (q, 2H, J=7.0 Hz), 7.80 (m, 4H), 8.15 (d, 8.5 Hz), 8.68 (s, 1H),9.13 (s, 2H), 9.38 (s, 2H), 9.66 (s, 1H); Anal. calc'd forC₁₄H₁₅N₃O₂.1.5 C₂F₃O₂H: C, 47.67; H, 3.88; N, 9.81. Found: C, 47.97; H,3.85; N, 9.78.

EXAMPLE 159 N-[7-(aminoiminomethyl)-1-naphthalenyl)propanamide,mono(trifluoroacetate)(salt)

The desired compound is prepared according to the procedures describedin examples 12 and 13.

Yield: 20 mg (23%) of white solid; MS m/z: 242 (M+H)⁺; ¹H NMR (DMSO, 300MHz): 1.18 (t, 3H, 7.4 Hz), 3.38 (m, 2H), 7.89 (m, 3H), 7.81 (dd, 1H,J1=8.4 Hz, J2=1.9 Hz), 7.87 (d, 1H, 8.5 Hz), 8.58 (s, 1H), 9.02 (s, 2H),9.47 (s, 2H), 9.97 (s, 1H). Anal. calc'd for C₁₄H₁₅N₃O.1.15 C₂F₃O₂H.0.25H₂O: C, 51.94; H, 4.45; N, 11.15; Found: C, 52.02; H, 4.24; N, 10.76.

EXAMPLE 160 N-[7-(aminoiminomethyl)-1-naphthalenyl)-2-methoxyacetamide,mono(trifluoroacetate)(salt)

The desired compound is prepared according to the procedures describedin Examples 12 and 13. Yield: 30 mg (30%) of white solid

MS m/z: 258 (M+H)⁺ ¹H NMR (DMSO, 300 MHz): 3.49 (s, 3H), 4.18 (s, 2H),7.80 (m, 3H), 7.93 (d, 1 H, 7.7 Hz), 8.47 (d, 1 H, 8.5 Hz), 8.47 (s,1H), 9.10 (s, 2H), 9.46 (s, 2H), 9.99 (s, 2H); Anal. calc'd forC₁₄H₁₅N₃O₂.1C₂F₃O₂H.1.25 H₂O: C, 48.80; H, 4.73; N, 10.67. Found: C,48.53; H, 4.34; N, 10.54; ¹H NMR (DMSO, 300 MHz): 2.16 (s, 3H), 4.85 (s,2H), 7.82 (m, 4H), 8.18 (d, 1H, J=8.18 Hz), 8.55 (s, 1H), 9.10 (s, 2H),9.44 (s, 2H), 10.24 (s, 1H); Anal. calc'd for C₁₅H₁₅N₃O₃.1C₂F₃O₂H.1 H₂O:C, 48.93; H, 4.35; N, 10.07. Found: C, 48.82; H, 4.27; N, 10.00.

EXAMPLE 161 N-[7-(aminoiminomethyl)-1-naphthalenyl]urea,mono(trifluoroacetate)(salt)

The desired compound is prepared according to the procedures describedin Examples 12 and 13. Yield: 35 mg (54%) of yellownish solid

MS m/z: 229 (M+H)⁺ ¹H NMR (DMSO, 300 MHz): 6.22 (s, 2H), 7.65 (m, 2H),7.77 (dd, J1=8.8 Hz, J2=1.5 Hz). 8.57 (s, 1H), 8.79 (s, 1H), 9.07 (s,2H), 9.49 (br, 2H); Anal. calc'd for C₁₂H₁₂N₄O.1 C₂F₃O₂H.0.75 H₂O: C,40.90; H, 3.33; N, 11.95. Found: C, 40.95; H, 3.64; N, 12.31.

EXAMPLE 162 N-[7-(aminoiminomethyl)-1-naphthalenyl]-2-hydroxyacetamide,mono(trifluoroacetate)(salt)

The desired compound is prepared according to the procedures describedin Examples 12 and 13. Yield: 24 mg (37%) of white solid

MS m/z: 244 (M+H)⁺ ¹H NMR (DMSO, 300 MHz): 4.18 (s, 2H), 5.82 (br, 1H).7.67 (m, 1H), 7.85 (m, 3H), 8.20 (d, 1H), 9.18 (s, 2H), 9.42 (s, 2H),9.89 (s, 1H); Anal. calc'd for C₁₃H₁₃N₃O₂.1 C₂F₃O₂H.0.75 H₂O: C, 48.59;H, 4.21; N, 11.33. Found: C, 48.64; H, 3.89; N, 11.25.

EXAMPLE 163 8-(2-pyrimidinylamino)-2-naphthalenecarboximidamide,bis(trifluoroacetate)(salt)

The desired compound is prepared according to the procedures describedin Examples 91A and 13. Yield: 28 mg (28%) of pale yellow solid

MS m/z: 264 (M+H)⁺ ¹H NMR (DMSO, 300 MHz): 6.90 (t, 1H, J1=J2=4.7 Hz),7.69 (d, J=7.8 Hz), 7.80 (1 H, J=8.1 Hz), 7.81 (1 H, dd, J1=8.4 Hz,J2=2.1 Hz), 8.08 (1H, dd, J1=7.4 Hz, J2=0.6 Hz), 8.14 (1H, d, J=8.5 Hz),8.49 (d, 2H), 8.75 (1H, d, J=1.7 Hz). 9.06 (s, 2H), 9.37 (s, 2H), 9.60(s, 1H); Anal. calc'd for C₁₅H₁₃N_(5.) 2.25 C₂F₃O₂H.0.25 H₂O: C, 44.67;H, 4.283.03; N, 13.36. Found: C, 44.49; H, 2.80; N, 13.40.

EXAMPLE 164 8-amino-2-naphthalenecarboximidamide,bis(trifluoroacetate)(salt)

To a solution of crude 8-amino-2-nitrile-naphthalene prepared asdescribed in Example 10 at room temperature in 10:1 pyridine:trimethylamine (10 mL) was bubbled hydrogen sulfide for 5 minutes andstirred at room temperature overnight. The reaction mixture was addedwater (50 mL) and the product was extracted into ethyl acetate (3×3 mL).The combined organic solvent was dried over magnesium sulfate, filteredand evaporated. The resulting yellow substance was taken up in acetone(30 mL) then added methyl iodide (2 mL). The reaction mixture was boiledfor 1 hour, then evaporated to dryness. To the resulting yellowsubstance in methanol (25 mL) was added ammonium acetate (100 mg) andstirred at room temperature overnight. The solvent was removed undervacuum and the product was purified via reverse phase chromatographyusing 0.1% TFA/water and 0.1% TFA/methanol as eluent.

MS m/z: 186 (M+H)⁺ ¹H NMR (DMSO, 300 MHz): 5.14 (br, 3H), 6.80 (dd, 1H,J1=7.8 Hz, J2=1 Hz), 7.17 (d, 1H, J=7.8 Hz), 7.40 (dd, 1H, J1=J2=7.8Hz), 7.70 (dd, 1H, J1=8.9 Hz, J2=2.1 Hz), 7.91 (d, 1H, J=8.5 Hz), 8.65(s, 1H), 8.95 (s, 2H), 9.23 (s, 2H); Anal. calc'd for C₁₁H₁₁N₃.2.5C₂F₃O₂H.0.75 H₂O: C, 39.72; H, 3.13; N, 8.69. Found: C, 40.01; H, 3.19;N, 8.88.

EXAMPLE 1656-(aminoiminomethyl)-N-[4-(aminomethyl)phenyl]-4-(2-pyrimidinylamino)-2-naphthalenecarboxamide,tris(trifluoroacetate)(salt) EXAMPLE 165A

A suspension of 2-nitrile-6-methyester naphthalene Example 8D (5.0 g, 23mmol) in concentrated sulfuric acid (50 mL) at −5° C. was added a solidpotassium nitrate. The colour of reaction mixture was gradually changedinto a dark brown. The reaction mixture was stirred for 15 minutes andwas poured into ice-water. Collected the precipitate and washed withwater. The crude product was recrystallized from ethyl acetate andethanol. Yield 4.3 g (68%) of pale yellow powder.

EXAMPLE 165B

To a solution of 2-nitrile-6-methylester-8-nitro-naphthalene, Example165A (3.5 g, 13.6 mmol) in a mixture of THF (100 mL) and ethyl acetate(120 mL) was added 10% Pd-C (350 mg). The reaction mixture was placedunder hydrogen at atmospheric pressure (balloon) and stirred at roomtemperature for 35 hour. The mixture was filtered through celite andsilica gel, washed with ethyl acetate and evaporated. The resultingsolid was washed with ether (20 mL).

Yield 2.20 g (71%) of yellow powder.

EXAMPLE 165C

A mixture containing 2-Nitrile-6-methylester-8-amino-naphthalene,Example 165B (2.8 g, 12.3 mmol), BINAP (116 mg, 0.186 mmol), Pd₂ (DBA)₃64 mg, 0.061 mmol), NaO-t-Bu (1.667 g, 17.6 mmol), 2-Bromopyrimidine(2.363 g, 14.9 mmol) and Toluene (80 mL) in an oven-dried flask undernitrogen, was stirred at room temperature for 10 minutes. The reactionmixture was heated to 80° C. for 1 hour. At the end of the reaction(TMC, hexanes+ethyl acetate=4:1), brine 9200 mL) was added. Extractedthe mixture with CH₂Cl₂. (4×250 mL). Evaporated the solvent. Yield 3.5 g(93%) of pale yellow powder.

EXAMPLE 165D

To a suspension of2-nitrile-6-methylester-8-N-(2-pyrimidine)-naphthalene, Example 165C(5.2 g, 17.1 mmol ) in ethanol (150 mL) was added potassium carbonate(3.54 g, 33.3 mmol) in water (200 mL). The resulting Suspension washeated at 120° C. for 2 hours, at that time all the suspension turnedinto a clear solution. The mixture is cooled down, then acidified with 2N HCl. The resulting precipitate was collected by filtration to yield4.5 g (90%) of pale yellow powder. No further purification was requiredfor the next step.

EXAMPLE 165E

To a cold (0° C.) solution of 2-nitrile-8-N-(2-pyrimidine)-6-carboxylicacid-naphthalene Example 165D (5.0 g, 17.2 mmol) in DMF (150 mL) wasadded DIEA (7.6 mL, 42.6 mmol) and O-(7-Azabenzotriazol-1-yl)-N, N, N′,N′-tetramethyluroniumhexafluorophosphate (9.8 g, 25.7 mmol) followed bytert-Butoxycarbonylamino-4-aminomethylaniline (5.74 g, 20 mmol). Theresulting reaction mixture was stirred for about 1 hour. The reactionwas quenched with water (200 mL) and the resulting precipitate wascollected by filtration to yield 3.26 g (38%) of pale yellow powder.

EXAMPLE 165F

To a solution of the substrate, Example 165E (3.0 g, 6.07 mmol) inpyridine (150 mL) was added triethylamine (9 mL). H₂S was passed for 10minutes and the resulting mixture was stirred at room temperature for 48hour. 100 mL of water was added to the reaction mixture and theprecipitate was Collected by filtration. Yield (3.0 g (93%) of yellowsolid.

EXAMPLE 165G

To a solution of the thioamide, Example 165F in acetone (200 mL) wasadded MeI (6 mL) and the mixture was stirred at room temperatureovernight. The mixture was evaporated to dryness to yield 1.2 g (78%,)of yellow solid.

EXAMPLE 165H6-(aminoiminomethyl)-N-[4-(aminomethyl)phenyl]-4-(2-pyrimidinylamino)-2-naphthalenecarboxamide,tris(trifluoroacetate)(salt)

To a solution of the imidate ester, Example 165G, (1.5 g, 2.2 mmol) inmethanol (50 mL) was added ammonium acetate (0.5 g, 6.4 mmol) andstirred at room temperature overnight. After evaporation of the solventthe residue was treated with ether (3×25 mL) and the ether was decanterdout. The residue was dissolved in a mixture of 10:1:1acetonitrile:water:acetic acid (50 mL). After addition of ether 100 mL),the Boc protected product precipitated as an acetate salt and wascolleted by filtration. The solid was added 1:1 TFA: methylene chloride(50 mL) containing thioanisole (0.5 mL). The reaction mixture wasstirred at room temperature overnight. The product was purified overRPC₁₈ chromatography using water: methanol with 0.1% TFA as eluent.Yield after lyophilization 0.5 g (54%) of pale yellow solid.

MS m/z: 412 (M+H)⁺ ¹H NMR (DMSO, 300 MHz): 4.02 (q, 2H, J=5.8), 6.94(dd, 1H, J12=J2=4.8 Hz), 7.45 (d, 2H, J=8.5 Hz), 7.84 (d, 2H, J=8.4 Hz),7.92 (dd, 1H, J1=8.5 Hz, J2=1.7 Hz), 8.13 (br, 3H), 8.30 (d, 1H, J=8.9Hz), 8.41 (s, 1H), 8.52 (d., 2H), 8.55 (s, 1H), 8.81 (s, 1H), 9.19 (s,2H), 9.43 (s, 2H), 9.75 (s, 1H), 10.62 (s, 1H); Anal. calc'd forC₂₃H₂₁N₇O.2.5 C₂F₃O₂H.1 H₂O: C, 43.49; H, 3.22; N, 11.83. Found: C,43.54; H, 3.34; N, 11.69.

EXAMPLE 1666-(aminoiminomethyl)-N-phenyl-4-(2-pyrimidinylamino)-2-naphthalenecarboxamidemono(trifluoroacetate)(salt)

The same procedure as described in Examples 165 substituting aniline for4-amino benzylamine.

MS m/z: 383 (M+H)⁺ ¹H NMR (DMSO, 300 MHz): 6.93-6.96 (m, 1H), 7.14 (dd,1H, J1=7.3 Hz, J2=7.4 Hz), 7.40 (dd, 2H, J1=J2=7.3 Hz), 7.80 (, d, 2H,J=8.1 Hz), 7.91 (d, 1H, J=8.9 Hz), 8.30 (d, 1H, J=9.0 Hz), 8.41 (s, 1H),8.52-8.54 (m, 3H), 8.80 (s, 1H), 9.16 (s, 2H), 9.45 (s, 2H), 9.78 (s,1H), 10.55 (s, 1H); Anal. calc'd for C₂₂H₁₈N₆O.2 C₂F₃O₂H.0.25 H₂O: C,50.78; H. 3.28; N, 13.31. Found: 50.85; H, 3.28; N, 13.31.

EXAMPLE 167N-[(4-(aminomethyl)phenyl]-6-[amino(hydroxyimino)methyl]-4-(2-pyrimidinylamino)-2-naphthalenecarboxamide,bis(trifluoroacetate)(salt)

To a suspension of compound, prepared in Example 165 E (0.20 g, 0.40mmol ) in methanol (40 mL) and water (20 mL) was added hydroxylaminehydro-chloride (112 mg, 1.75 mmol) and sodium carbonate (85 mg, 0.80mmol), the reaction mixture was stirred for 48 hours at roomtemperature, TLC showed no reaction. The reaction mixture was heated atreflux for 10 hours and removed the most of the solvents, theprecipitate was collected by filtration, gave 1.2 g of pale yellowsolid. The solid was dissolved in 1:1 TFA+CH₂Cl₂ (30 mL) and stirred atroom temperature for 24 hours. The solvents was removed under vaccuumand the residue was loaded to a R18 reverse phase column. The fractionwas lyophilized and yielded a pale yellow powder (80 mg, 66%).

MS m/z: 428 (M+H)⁺ ¹H NMR (DMS0, 300 MHz): 4.02 (q, 2H, J=6.1 Hz), 6.92(dd, 1H, J1=J2=5.1 Hz), 7.46 (d, 2H, 8.4 Hz), 7.85 (d, 2H, J=8.5 Hz),7.88 (d, 1H, 9 Hz), 8.12 (br, 3H), 8.22 (d, 1H, J=8.9 Hz), 8.40 (s, ¹H),8.48 (s, 1H), 8.51 (d, 2H, J=4.8 Hz), 8.64 (s, 1H), 9.74 (s, 2H), 10.61(s, 2H); Anal. calc'd for C₂₃H₂₁N₇O₂.2.9 C₂F₃O₂H.1.25 H₂O: C, 44.31; H,3.41; N, 12.56; F, 21.17. Found: C, 44.08; H, 3.30; N, 12.50, F, 21.25.

EXAMPLE 1686-(aminoiminomethyl)-N-[4-(hydroxymethyl)phenyl]-4-(2-pyrimidinylamino)-2-naphthalenecarboxamide,mono(trifluoroacetate)(salt)

The desired compound is prepared as described in Example 165 using4-amino benzyl alcohol instead of 4-amino benzylamine.

MS m/z: 413 (M+H)⁺ ¹H NMR (DMSO, 300 MHz): 4.48 (s, 2H), 6.94 (dd, 1H,2H, J=8.8 Hz), J1=J2=4.8 Hz), 7.32 (d, 2H, J=8.8 Hz), 7.90 (dd, 1H,J1=8.5 Hz, J2=1.7 Hz), 8.28 (d, 2H, J=8.8 Hz), 8.41 (s, 1H), 8.54 (d,2H, J=4.8 Hz), 8.55 (dd, 1H, J=1.3 Hz), 8.80 (s, 1H), 9.08 (s, 2H), 9.43(s, 2H), 9.73 (s, 1H), 10.48 (s, 1H); Anal. calc'd for C₂₃H₂ON₆O₂: C,49.06; H, 3.83; N, 12.81; F, 16.50. Found: C, 48.74; H, 3.86; N, 12.63,F, 16.54.

EXAMPLE 170 Methyl[3-[[[4-(aminomethyl)phenyl]amino]carbonyl]-7-[4-amino(hydroxyimino)methyl]-1-naphthalenyl]carbamate,bis(trifluoroacetate)(salt) EXAMPLE 170A

To a suspension of the nitrile, Example 141D (213 mg, 0.45 mmol) andhydroxylamine hydrochloride (338 mg, 4.86 mmol) in methanol (40 mL)water (5 mL) was added potassium carbonate (538 mg, 3.9 mmol) stirred atroom temperature overnight. The solvent was evaporated and the resultingsolid was washed with ether and hexanes to yield the product as whitesolid 153 mg (62%).

MS (ECI) m/z 508 (M+H)⁺.

EXAMPLE 170B Methyl[3-[[[4-(aminomethyl)phenyl]amino]carbonyl]-7-[4-amino(hydroxyimino)methyl]-1-naphthalenyl]carbamate,bis(trifluoroacetate)(salt)

The Boc protected substrate, Example 170A was added 3 mL of 4 N HCl indioxane and stirred at room temperature for 20 minutes. The solvent wasevaporated under vacuum and the product was separated on MPLC with acolumn of RPC₁₈ using methanol-water+0.1% TFA as eluent. Yield of whitesolid 117 mg (79%).

MS (ECI) m/z 408 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆) δ 3.77 (S, 3H), 4.03(s, 2H), 4.01 (q, J=5.9 2H), 7.46 (d, J=8.5 Hz, 2H), 7.86 (d, J=8.5 Hz,2H), 7.90 (dd, J₁=8.5, Hz, J₂=1.4 Hz, 1H), 8.09-8.15 (m, 4H), 8.17 (d,J=8.4 Hz, 1H), 8.29 (s, 1H), 8.42 (s, 1H), 8.56 (s, 1H), 9.80 (s, 1H),10.62 (s, 1H); Anal. calc'd for C₂₁H₂₁N₅O₄.2.5 TFA.0.5 H₂O: C, 44.52; H,3.52; F, 20.3; N, 9.98. Found: C, 44.78; H, 3.57; F, 19.82; N, 9.87.

EXAMPLE 1716-[amino(hydroxyimino)methyl]-N-phenyl-2-naphthalenecarboxamide

The title compound is prepared as described by Judkins et al., SyntheticCommunications 26 (23), 4351-4367 (1996). The compound prepared inExample 55C (0.1 g, 0.36 mmole) is dissolved in a 10:1 mixture ofToluene:methanol to which is added hydroxylamine hydrochloride (3.6mmole) and potassium tert-butoxide (3.6 mmole). The resulting slurry isrefluxed for 17 hr., cooled, solvents removed under vacuum. The residueis taken up in distilled water (30 ml) extracted with ethyl acetate(2×100 ml). The combined organic extracts are washed with 10% NaCl (50ml), dried over anhydrous Na₂SO₄. The sample is filtered of drying agentand the solvent removed under vacuum leaving a white solid (65 mg). Thematerial is purified by medium pressure reverse phase chromatography asdescribed in Example 1. The title compound is obtained as white solid(45 mg)

MS (m/z) M+H⁺: 306; ¹H NMR (DMSO-d₆): 10.51 (s, 1H), 9.32 (s, OH), 8.70(s, 1H), 8.57 (s, 1H), 8.34 (d, 1H), 8.25 (d, 1H), 8.17 (dd, 1H), 7.90(dd, 1H), 7.83 (d, 2H), 7.40 (dd, 2H), 7.15 (dd, 1H), 6.25 (bs, 2H).Analysis: calc'd for C₂₀H₁₆N₃O₄F₃: C, 57.28, H, 3.85, N, 10.02; Found C,56.89, H, 3.65, N, 9.90.

EXAMPLE 174 8-(2-pyridinylamino)-2-naphthalenecarboximidamide,bis(trifluoroacetate) salt EXAMPLE 174A

To a solution of the product from 11D (168 mg, 1.00 mmol) in 5 mLtoluene was added 2-bromopyridine (0.105 mL, 1.1 mmol), NaOtBu (135 mg,1.4 mmol), Pd₂dba₃ (92 mg, 0.1 mmol), and P (o-tolyl)₃ (122 mg, 0.4mmol), and the reaction was stirred for 24 hours at 100° C. The reactionwas cooled, and the crude reaction mixture was chromatographtd on SiO₂using 50% ethyl acetate/hexanes as eluent to yield 80 mg (33%) of thedesired compound.

MS (DCI (NH₃)) m/z 246 (M+H)⁺.

EXAMPLE 174B 8-(2-pyridinylamino)-2-naphthalenecarboximidamide,bis(trifluoroacetate) salt

The product from Example 174A (121 mg, 0.493 mmol) was dissolved in THF(2 mL) and 0.543 mL of a 1 M solution of LiN (TMS)₂ in THF was added.The reaction was stirred for 5 min, and TMSCl (0.069 mL, 0.543 mmol) wasadded. After stirring for 30 min, another 1.09 mL of the 1 M solution ofLiN (TMS)₂ was added. The reaction was stirred for 18 hours, and 10 mLof a 2 M aq. HCl solution was added. The reaction was stirred foranother 24 hours, and was basified with saturated aq. Na₂CO₃. Themixture was extracted with 3×ethyl acetate, and the extracts were washedwith brine, dried over Na₂SO₄, and condensed. The crude product waspurified by reverse-phase HPLC to yield the desired compound (21 mg,7%): m.p. 137-147° C.

MS (DCI (NH₃) m/z 263 (M+H)⁺; ¹H NMR (300 MHz, DMSO) δ 9.98 (br s, 1H),9.46 (br s, 2H), 9.27 (br s, 2H), 8.74 (s, 1H), 8.21 (d, J=9 Hz, 1H),8.11 (d, J=6 Hz, 1H), 8.02 (d, J=9 Hz, 1H), 7.81-7.95 (m, 3H), 7.75 (dd,J=9, 9 Hz, 1H), 7.16 (m, 1H), 6.95 (m, 1H), 2.55 (s, 3H); Anal. calc'dfor C₁₆H₁₄N₄.3.1C₂HF₃O₂: C, 43.30; H, 2.80; N, 9.10. Found: C, 43.14; H,3.04; N, 9.90.

EXAMPLE 1766-[4-[(hydroxymethyl)phenyl]methoxy]-2-naphthalenecarboximidamide,methanesulfonate(salt) EXAMPLE 176A

To a solution of NaH (60% in mineral oil, 1.17 g, 29.3 mmol) in THF (50mL) was added 4-bromobenzyl alcohol (5.22 g, 27.9 mmol) in THF (50 mL),and the reaction was stirred at room temperature for 20 minutes.p-Methoxybenzyl chloride (4.07 mL, 30 mmol) was then added, and thereaction was stirred at 50° C. for 2 hours. The mixture was poured intowater and extracted with 3×diethyl ether, and the extracts were washedwith brine, dried over Na₂SO₄, and condensed. The crude reaction mixturewas chromatographed on SiO₂ using hexanes as eluent, to yield 7.39 g(86%) of the desired compound.

MS (DCI (NH₃)) m/z 326 (M+NH₄)⁺; ¹H NMR (300 MHz, CDCl₃) δ 7.47 (d, 2H),7.28 (d, 2H), 7.23 (d, 2H), 6.90 (d, 2H), 4.48 (s, 3H), 4.47 (s, 2H),3.91 (s, 3H).

EXAMPLE 176B

To a solution of the product from Example 176A (6.80 g, 22.13 mmol) inTHF (100 mL) and hexanes (20 mL) at −100° C. was added a 2.5 M solutionof BuLi (8.85 mL, 22.13 mmol), and the reaction was stirred for 2minutes. DMF (3.43 mL, 44.3 mmol) was then added, and the reaction waswarmed to room temperature. The mixture was poured into water andextracted with 3× diethyl ether, and the extracts were washed withbrine, dried over Na₂SO₄, and condensed. The crude reaction mixture wastaken up in methanol (100 mL) and NaBH₄ (1.0 g, 26.2 mmol) was added inportions. A few drops of water were added, and the mixture condensed.The residue was chromatographed on SiO₂ using 20% ethyl acetate/hexanesas eluent, to yield 3.32 g (58%) of the desired compound.

MS (DCI (NH₃)) m/z 276 (M+NH₄)⁺; ¹H NMR (300 MHz, CDCl₃) δ 7.38 (s, 4H),7.29 (d, 2H), 6.90 (d, 2H), 4.70 (s, 2H), 4.54 (s, 2H), 4.49 (s, 2H),3.81 (s, 3H), 1.62 (s, 1H).

EXAMPLE 176C

To a solution of the product from Example 176B (193 mg, 0.747 mmol), theproduct from Example 28A (139 mg, 0.822 mmol), and Ph₃P (216 mg, 0.822mmol) in THF (10 mL) at 0° C. was added dimethylazodicarboxylate(0.129mL, 0.822 mmol), and the reaction was stirred for 90 minutes atroom temperature. The Crude reaction mixture was condensed, and theresidue was chromatogriaphed on SiO₂ using 10% ethyl acetate/hexanes aseluent, to yield 225 mg (74%) of the desired compound.

MS (DCI (NH₃)) m/z 427 (M+NH₄)⁺; ¹H NMR (300 MHz, CDCl₃) δ 8.15 (s, 1H),7.81 (d, 1H), 7.77 (d, 1H), 7.58 (dd, 1H), 7.48 (d, 2H), 7.42 (d, 2H),7.02-7.15 (m, 4H), 6.90 (d, 2H), 5.21 (s, 2H), 4.56 (s, 2H), 4.51 (s,2H), 3.91 (s, 3H).

EXAMPLE 176D

To a solution of the product from Example 176C (220 mg, 0.537 mmol) inCH₂Cl₂ (40 mL) and water (7 mL) was added DDQ (244 mg, 1.07 mmol), andthe reaction was stirred for 90 minutes. The crude reaction mixture wastaken up in CH₂Cl₂, washed with 2× aqueous NaHCO₃ and brine, dried overNa₂SO₄, and condensed. The residue was chromatographed on SiO₂ using 50%ethyl acetate/hexanes as eluent, to yield 89 mg (57%) of the desiredcompound.

MS (DCI (NH₃)) m/z 307 (M+NH₄)⁺; ¹H NMR (300 MHz, CDCl₃) δ 8.15 (s, 1H),7.81 (d, 1H), 7.77 (d, 1H), 7.57 (dd, 1H), 7.49 (d, 2H), 7.41 (d, 2H),7.33 (dd, 1H), 7.21 (d, 1H), 5.21 (s, 2H), 4.74 (s, 2H), 1.63 (br s,1H);

EXAMPLE 176E6-[4-[(hydroxymethyl)phenyl]methoxy]-2-naphthalenecarboximidamide,methanesulfonate(salt)

The desired compound was prepared from Example 176D and the procedure ofExample 55D.

MS (DCI/NH₃) m/z 307 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆) δ 2.31 (s, 3H),4.52 (s, 2H), 5.25 (s, 2H), 7.37 (d, 2H), 7.39 (dd, 1H), 7.47 (d, 2H),7.59 (d, 1H), 7.79 (dd, 1H), 8.00 (d, 1H), 8.03 (d, 1H), 8.41 (s, 1H),8.89 (br s, 2H), 9.34 (br s, 2H); Anal. calc'd for C₁₉H₁₈N₂O₂.1.15CH₄SO₃: C, 58.06; H, 5.46; N, 6.72. Found: C, 58.24; H, 5.62; N, 6.59.

EXAMPLE 177N-hydroxy-8-(2-pyrimidinylamino)-2-naphthalenecarboximidamide,mono(trifluoroacetate)(salt)

The desired compound is prepared from the nitrile described in Example163 and utilizing the procedure described in Example 167. Yield as awhite powder: 50 mg

MS m/z: 280 (M+H)⁺; ¹H NMR (DMSO, 300 MHz): 6.90 (dd, 1H, J1=J2=5.2 Hz),7.45 (m, 3H), 8.0 (d, 1H, J=8.5 Hz), 8.14 (d, 1H, J=8.4 Hz), 8.49 (d,J=5.3 Hz), 8.61 (s, 1H), 9.58 (s, 1H); Anal. calc'd for C₁₅H₁₃N₅O.2.0C₂F₃O₂H.0.5 H₂O: C, 44.20; H, 3.12; N, 13.56. Found: C, 44.24; H, 2.94;N, 13.49.

EXAMPLE 179 6-(2-pyridinylethynyl)-2-naphthalenecarboximidamide,mono(trifluoroacetate)(salt) EXAMPLE 179A

Using the product obtained in Example 28B, 2-ethynylpyridine (LancasterChemical Corp.) and the procedure described in Example 121A, the desiredcompound was obtained.

MS (DCI/NH₃) m/z 255 (M+H)⁺.

EXAMPLE 179B

Using the product obtained in Example 179A and the procedure describedin Example 94D the desired compound was obtained.

MS (DCI) m/z 272 (M+H)⁺; ¹H NMR (300 MHz, DMSO) δ 7.45-7.50 (m, 1H),7.72 (d, 1H), 7.82 (dd, 1H), 7.86-7.92 (m, 2H), 8.18 (d, 1H), 8.22 (d,1H), 8.42 (s, 1H), 8.54 (s, 1H), 8.68 (m, 1H), 9.25 (s, 2H), 9.49 (s,2H); Anal. calc'd for C₂₀H₁₄F₃N₃O₂.0.25 H₂O: C, 61.62; H, 3.75; N.10.78. Found: C, 61.72; H, 3.64; N, 10.66.

EXAMPLE 1806-(aminoiminomethyl)-N-phenyl-4-(tetrahydro-3-furanyl)-2-naphthalenecarboxamide,monohydrochloride EXAMPLE 180A

The desired compound was prepared from the product from Example 152 bythe procedure of Example 62A.

MS (DCI/NH₃) m/z 340 (M−H₂O)⁺.

EXAMPLE 180B

The desired compound was prepared from the product from Example 180A bythe procedure of Example 62B.

MS (DCI/NH₃) m/z 343 (M+H)⁺.

EXAMPLE 180C

The desired compound was prepared from Example 1880B and the procedureof Example 55D.

MS (DCI/NH₃) m/z 360 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆) δ 2.20 (m, 1H),2.52 (m, 1H), 3.85 (dd, 1H), 3.94 (ddd, 1H), 4.08 (ddd, 1h), 4.26 (dddd,1H), 4.39 (dd, 1H), 7.14 (t, 1H), 7.40 (t, 2H), 7.81 (d, 2H), 7.95 (d,1H), 8.08 (s, 1H), 8.32 (d, 1H), 8.59 (s, 1H), 8.79 (s, 1H), 9.25 (br s,2H), 9.61 (br s, 2H); Anal. calc'd for C₂₂H₂₁N₃O₂.2.6 HCl: C, 58.18; H,5.24; N, 9.25. Found: C, 58.21; H, 4.91; N, 9.13.

EXAMPLE 1816-[amino(hydroxyimino)methyl]-N-phenyl-4-(2-pyridinylamino)-2-naphthalenecarboxamide

Prepared in a similar manner as described in Example 177 using thematerial prepared in Example 166.

MS m/z: 399 (M+H)⁺; ¹H NMR (DMSO, 300 MHz): 6.88 (dd, 1H, 4.7 Hz), 7.11(dd, 1H, J1=J2=7.5 Hz), 7.37 (dd, 2H, J1=J2=7.5 Hz), 7.82 (d, 2H, J=8.8Hz), 7.94 (dd, 1H, J1=8.5 Hz, J2=1.4 Hz), 8.04 (d, 1H, J=8.8 Hz), 8.31(s, 1H), 8.43 (dd, 1H, J=14 Hz), 8.74 (d, 2H, J=4.7 Hz), 8.52 (s, 1H),9.55 (s, 1H), 9.85 (s, 2H), 10.41 (s, 1H); Anal. calc'd forC₂₂H₁₈N₆O₂.0.4 H₂O: C, 65.14; H, 4.67; N, 20.72. Found: C, 65.57; H,4.45; N, 20.18.

EXAMPLE 182 Methyl4-[[[7-amino(hydroxyimino)methyl]-2-naphthalenyl]oxy]methyl]benzoate

The resulting product from Example 213A (110 mg, 0.347 mmol),hydroxylamine hydrochloride (26.5 mg, 0.381 mmol), triethylamine (53 μl,0.381 mmol) and N,N-dimethylformamide (12 mL) were combined in a fourinch glass pressure tube. The tube was sealed and heated for 24 hours at80° C. The tube was cooled to room temperature and additionalhydroxylamine hydrochloride (48.1 mg, 0.693 mmol) and triethylamine(96.6 μl, 0.693 mmol) in N,N-dimethylformamide (2 mL) was added. Thetube was resealed and heated for 24 hours at 80° C. The addition, asabove, was repeated a second time, the tube was resealed and heated for72 hours at 80° C. The reaction mixture was concentrated to a solidresidue which was purified by column chromatography on silica gel (60 g)eluted with 15% acetone in methylene chloride to yield the targetcompound as a white solid (43 mg, 50% based on recovered startingmaterial).

MS (DCI (NH₃)) m/z 351 (M+H)⁺; ¹H NMR NMR (300 MHz, DMSO-d₆) δ 3.860)(s, 3H), 5.349 (s, 2H), 5.860 (s, 2H), 7.280 (dd, 1H), 7.381 (d, 1H),7.660 (d, 2H), 7.688 (dd, 1H), 7.805 (d, 1H), 7.850 (d, 1H), 8.010 (d,2H), 8.070 (s, 1H), 9.724 (s, 1H); Anal. calc'd for C₂₀H₁₈N₂O₄.0.15 H₂O:C, 68.04; H, 5.22; N, 7.93. Found: C, 68.06; H, 5.05; N, 7.87.

EXAMPLE 184N-[4-(aminocarbonyl)phenyl]-6-(aminoiminomethyl)-2-naphthalenecarboxamide,mono(trifluoroacetate) salt EXAMPLE 184A

A suspension of the product obtained in Example 8A (300 mg, 1.39 mmol)and 5 mL dichloromethane was added dropwise to a 0° solution of4-aminobenzamide (207 mg, 1.52 mmol), trimethylamine (0.44 mL, 3.2mmol), and 10 mL dichloromethane. The reaction mixture was stirred for0.5 hour at 0° and for 18 hours at room temperature. Excess ether wasadded with stirring and the resultant solid was filtered, washed with 1N HCl, water, and was dried under vacuum to afford the desired compound.

MS (DCI) m/z 333 (M+NH₃)⁺.

EXAMPLE 184BN-[4-(aminocarbonyl)phenyl]-6-(aminoiminomethyl)-2-naphthalenecarboxamide,mono(trifluoroacetate) salt

Using the product obtained in Example 184A and the procedure describedin Example 4C the desired compound was obtained.

MS (DCI) m/z 333 (M+H)⁺; ¹H NMR (300 MHz, DMSO) δ 10.76 (S, 1H), 9.51(S, 2H), 9.14 (S, 2H), 8.74 (S, 1H), 8.56 (S, 1H), 8.33 (D, 1H, J=8.8Hz), 8.26 (D, 1H, J=8.8 HZ Hz), 8.16 (DD, 1H, J=8.46, 1.11 Hz), 7.91 (M,6H), 7.31 (S, 1H); Anal. calc'd for C₂₀H₁₇F₃N₄O₄.1.5 H₂O: C, 53.28; H,4.26; N, 11.83. Found: C, 53.47; H, 3.86; N, 11.96.

EXAMPLE 185 Methyl 2-[[6-(aminoiminomethyl)-2-naphthalenyl]oxy]acetate,mono(trifluoroacetate)(salt) EXAMPLE 185A

7-methoxy-2-cyanonaphthalene, (2.79 g, 5.23 mmol) and tetrabutylammoniumiodide (17 mg, 0.157 mmol) were combined in a mixture of benzene (35 mL)and cyclohexanes (17.5 mL). The resulting solution was added to arapidly stirring, cooled (ice/water) suspension of aluminum triiodide(6.21 g, 15.23 mmol) in a mixture of benzene (35 mL) and cyclohexanes(17.5 mL) under an inert atmosphere. After the addition, the resultingsuspension was heated at reflux for 2.5 hours. The heating was removedand after cooling to near room temperature, the reaction mixture wascooled in an ice bath and quenched by the addition of water (100 mL).The resulting mixture was further diluted with 2 M aqueous sodiumthiosulfate solution (50 mL) and extracted with ethyl acetate (3×80 mL).The combined organic layers were dried and evaporated. The resultingsolid was dissolved in a minimum of hot ethyl acetate, diluted hot withhexanes to the cloud point and placed in a refrigerator for 2 hours. Thedesired compound was collected by filtration, (1.99 g, 77%).

MS (DCI (NH₃)) m/z 187 (M+NH₄)⁺.

EXAMPLE 185B

The resulting product from Example 185A (217 mg, 1.283 mmol) wascombined with cesium carbonate (460 mg, 1.411 mmol) andtetrabuthylammonium iodide (catalytic) in DMF (7 mL). To this was addedt-butyl bromoacetate (193 μL, 1.283 mmol) and the resulting mixture wasstirred 2 hours under an inert atmosphere. The reaction mixture wasdiluted with water (100 mL) and extracted with ethyl acetate (2×50 mL).The combined organic layers were dried and evaporated. The residue waspurified by column chromatography to yield the desired compound as anoil (332 mg, 91%):

MS (DCI (NH₃)) m/z 284 (M+H)⁺, 301 (M+NH₄)⁺.

EXAMPLE 185C Methyl 2-[[6-(aminoiminomethyl)-2-naphthalenyl]oxy]acetate,mono(trifluoroacetate)(salt)

The product from Example 185B (323 mg, 1.140 mmol) was dissolved inanhydrous methanol (32 mL) under an inert atmosphere and cooled to 0° C.Anhydrous hydrogen chloride was bubbled into the solution until itbecame saturated. The reaction was stirred for 15 minutes at 0° C. andsaturated again with anhydrous hydrogen chloride. After stilling for anadditional 20 minutes at 0° C. the solution was saturated one final timewith anhydrous hydrogen chloride and stirred 18 hours while warming toroom temperature. The reaction was evaporated to a solid and dried underhigh vacuum for 2 hours. The solid was slurried in methanol (64 mL),ammonium acetate (220 mg, 2.850 mmol) was added, and the mixture washeated at reflux 2 hours. The reaction was evaporated and purified byreverse phase chromatography to give the desired compound (265 mg, 90%).

MS (DCI (NH₃)) m/z 259 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆) δ 3.735 (s,3H), 4.995 (s, 2H), 7.430 (dd, 1H), 7.458 (s, 1H), 7.669 (dd, 1H), 8.025(d, 1H), 8.095 (d, 1H), 8.325 (d, 1H), 9.090 (br s, 1H), 9.410 (br s,1H; Anal. calc'd for C₁₄H₁₄N₂O₃. (C₂HO₂F₃) 1.05: C, 51.16; H, 4.01; N,7.41. Found: C, 51.35; H, 3.98; N, 7.48.

EXAMPLE 1866-(aminoiminomethyl)-N-(2-thiazonyl)-2-naphthalenecarboxamide,monohydrochloride EXAMPLE 186A

The above product was prepared in the manner of Example 8A using2-aminothiazole.

MS (APCI) m/z (M+H)⁺ 280.

EXAMPLE 186B6-(aminoiminomethyl)-N-(2-thiazolyl)-2-naphthalenecarboxamide,monohydrochloride

The above was prepared from Example 1B.

MS (APCI) m/z (M+H)⁺ 297; ¹H-NMR (300 MHz, DMSO-d₆) δ 12.88 (s, 1H),9.59 (s, 2H), 9.30 (s, 2H), 8.87 (s, 1H), 8.59 (s, 1H), 8.32-8.22 (m,4H), 7.93 (dd, J=1.8, 8.4 Hz, 1H), 7.61 (d, J=3.3 Hz, 1H), 7.33 (d,J=3.3 Hz, 1H); Anal. calc'd for C₁₅H₁₃N₄OClS 2/5 HCl: C, 52.03; H, 3.89;N, 16.18. Found: C, 52.01; H, 3.88; N, 16.12.

EXAMPLE 1876-(aminoiminomethyl)-N-(6-methoxy-3-pyridinyl)-2-naphthalenecarboxamide,monohydrochloride EXAMPLE 187A

The above product was prepared in the manner of Example 8A using5-amino-2-methoxypyridine.

MS (APCI) m/z (M+H)⁺ 304.

EXAMPLE 187B6-(aminoiminomethyl)-N-(6-methoxy-3-pyridinyl)-2-naphthalenecarboxamide,monohydrochloride

The above was prepared as described Example 1B (144D).

MS (CI) m/z (M+H)⁺ 321; ¹H-NMR (300 MHz, DMSO-d₆) δ 10.71 (s, 1H), 9/60(s, 2H), 9.41 (s, 2H), 8.76 (s, 1H), 8.60 (s, 2H), 8.30 (d, J=9, 1H),8.25-8.12 (m, 4H), 7.93 (dd, J=1.8, 8.7 Hz, 1H), 6.89 (d, J=9.0 Hz, 1H),3.87 (s, 3H); Anal. calc'd for C₂₀H₁₇N₄O₄F₃ 1/2 TFA: C, 51.47; H, 3.60;N, 11.45. Found: C, 51.39; H, 3.88; N, 11.65.

EXAMPLE 1886-(aminoiminomethyl)-N-(1,3-benzodioxol-5-yl)-2-naphthalenecarboxamide,mono(trifluoroacetate)(salt) EXAMPLE 188A

The above product was prepared in the manner of Example 8A using3,4-methylenedioxyaniline.

MS (APCI) m/z (M+H)⁺ 317.

EXAMPLE 188B

The above was prepared as described Example 1B.

MS (CI) m/z (M+H)⁺ 334; ¹H-NMR (300 MHz, DMSO-d₆) δ 9.70 (s, 1H), 8.20(s, 2H), 9.96 (s, 1H), 7.81-87.63 (m, 3H), 7.31 (dd, J=1.8, 8.4 Hz, 1H),7.11 (d, J=4.2 Hz, 1H), 6.91 (dd, J=4.5, 10.8 Hz), 6.4 (d, J=8.4 Hz,1H), 5.59 (s, 2H); Anal. calc'd for C₂₁H₁₆N₃O₃F₃ 3/5 TFA: C, 55.44; H,3.48; N, 8.77. Found: C, 55.44; H, 3.52; N, 8.85.

EXAMPLE 1896-(aminoiminomethyl)-N-(1,2,3,4-tetrahydro-2,4-dioxo5-pyrimidinyl)-2-naphthalenecarboxamide,monohydrochloride EXAMPLE 189A

The above product was prepared in the manner of Example 8A using5-aminouracil.

MS (APCI) m/z (M−H)⁺ 305.

EXAMPLE 189B6-(aminoiminomethyl)-N-(1,2,3,4-tetrahydro-2,4-dioxo5-pyrimidinyl)-2-naphthalenecarboxamide,monohydrochloride

The above was prepared as described in Example 1B.

MS (CI) m/z (M+H)⁺ 324; ¹H-NMR (300 MHz, DMSO-d₆) δ 11.50 (s, 1H),10.90(m, 1H), 9.53 (s, 3H), 9.21 (s, 2H), 8.70 (s, 1H), 8.55 (s, 1H),8.33 (d, J=8.4 Hz, 1H), 8.20 (d, J=8.7 Hz, 1H), 8.13-8.09 (m, 2H), 8.00(s, 1H), 7.88 (dd, J=1.8, 8.4 Hz, 1H); Anal. calc'd for C₁₆H₁₄N₅O₃Cl 2/5HCl: C, 51.49; H, 3.88; N, 18.76. Found: C, 51.87; H, 4.01; N, 17.68.

EXAMPLE 1906-(aminoiminomethyl)-N-(3,5-difluorophenyl)-2-naphthalenecarboxamide,mono(trifluoroacetate)(salt) EXAMPLE 190A

The above product was prepared in the manner of Example 8A using3,5-difluoroaniline.

MS (APCI) m/z (M−H)⁺ 307.

EXAMPLE 190B6-(aminoiminomethyl)-N-(3,5-difluorophenyl)-2-naphthalenecarboxamide,mono(trifluoroacetate)(salt)

The above was prepared as described in Example 1B.

MS (CI) m/z (M+H)⁺ 326; 1H-NMR (300 MHz, DMSO-d₆) δ 10.93 (s, 1H), 9.53(s, 2H), 9.34 (s, 2H), 8.71 (s, 1H), 8.58 (s, 1H), 8.33 (d, J=8.4 Hz,1H), 8.26 (d, J=8.7 Hz, 1H), 8.14 (m, 1H), 7.92 (dd, J=0.9, 8.1 Hz, 1H),7.61 (d, J=7.8 Hz, 2H), 7.04-6.97 (m, 1H); Anal. calc'd for C₂₀H₁₄N₃O₂F₅2/5 TFA: C, 54.92; H, 3.21; N, 9.42. Found: C, 54.96; H, 3.36; N, 9.37.

EXAMPLE 1916-(aminoiminomethyl)-N-(1H-pyrazol-3-yl)-2-naphthalenecarboxamide,mono(trifluoroacetate)(salt) EXAMPLE 191A

The above product was prepared in the manner of Example 8A using3-aminopyrazole.

MS (APCI) m/z (M+H)⁺ 263.

EXAMPLE 191B6-(aminoiminomethyl)-N-(1H-pyrazol-3-yl)-2-naphthalenecarboxamide,mono(trifluoroacetate)(salt)

The above was prepared as described in Example 1B.

MS (CI) m/z (M+H)⁺ 280; 1H-NMR (300 MHz, DMSO-d₆) δ 11.13 (s, 1H), 9.55(s, 2H), 9.37 (s, 2H), 8.75 (s, 1H), 8.55 (s, 1H), 8.23 (d, J=8.4 Hz,1H), 8.12 (s, 2H), 7.90 (d, J=8.4 Hz, 1H), 7.70 (s, 1H), 6.69 (s, 1H);Anal. calc'd for C₁₇H₁₄N₅O₃F₃ 7/10 TFA: C, 46.53; H, 3.12; N, 14.70.Found: C, 46.47; H, 3.16; N, 14.85.

EXAMPLE 1926-(aminoiminomethyl)-N-(5-methyl-3-isoxazolyll)-2-naphthalenecarboxamide,mono(trifluoroacetate)(salt) EXAMPLE 192A

The above product was prepared in the manner of Example 8A using3-amino-5-methylisoxazole.

MS (APCI) m/z (M+H)⁺ 278.

EXAMPLE 192B6-(aminoiminomethyl)-N-(5-methyl-3-isoxazolyll)-2-naphthalenecarboxamide,mono(trifluoroacetate)(salt)

The above was prepared as described in Example 1B.

MS (CI) m/z (M+H)⁺ 295; 1H-NMR (300 MHz, d₆-DMSO) δ 11.62 (s, 1H), 9.52(s, 2H), 9.33 (s, 2H), 8.78 (s, 1H), 8.55 (dd, 1H), 8.31-8.16 (m, 3H),7.90 (dd, 1H), 6.81 (s, 1H), 2.44 (s, 3H); Anal. calc'd forC₁₈H₁₅N₄O₄F₃: C, 52.95; H, 3.70; N, 13.72. Found: C, 52.73; H, 3.64; N,13.24.

EXAMPLE 193 6-(aminoiminomethyl)-N-(pyrazinyl)-2-naphthalenecarboxamide,mono(trifluoroacetate)(salt) EXAMPLE 193A

The above product was prepared in the manner of Example 8A using2-aminopyrazine.

MS (APCI) m/z (M−H)⁺ 275.

EXAMPLE 193B6-(aminoiminomethyl)-N-(pyrazinyl)-2-naphthalenecarboxamide,mono(trifluoroacetate)(salt)

The above was prepared as described in Example 1B.

MS (CI) m/z (M+H)⁺ 292; ¹H-NMR (300 MHz, d₆-DMSO) δ 11.41 (s, 1H), 9.52(s, 2H), 9.49 (s, 1H), 9.27 (s, 2H), 8.83 (s, 1H), 8.56 (s, 1H),8.53-8.46 (m, 2H), 8.30 (d, 1H), 8.23 (s, 2H), 7.90 (dd, 1H); Anal.calc'd for C₁₈H₁₄N₅O₃F₃: C, 49.36; H, 3.16; N, 15.15 1/2 TFA. Found: C,49.53; H, 3.22; N, 14.87.

EXAMPLE 1946-(aminoiminomethyl)-N-(6-methyl-2-pyridinyl)-2-naphthalenecarboxamide,mono(trifluoroacetate)(salt) EXAMPLE 194A

The above product was prepared in the manner of Example 8A using2-amino-6-methylpyridine.

MS (APCI) m/z (M+H)⁺ 288.

EXAMPLE 194B6-(aminoiminomethyl)-N-(6-methyl-2-pyridinyl)-2-naphthalenecarboxamide,mono(trifluoroacetate)(salt)

The above was prepared as described in Example 1B.

MS (CI) m/z (M+H)⁺ 305; ¹H-NMR (300 MHz, d₆-DMSO) δ 11.02 (s, 1H), 9.53(s, 2H), 9.37 (s, 2H), 8.80 (s, 1H), 8.55 (s, 1H), 8.29 (d, 1H), 8.20(s, 2H), 8.07 (d, 1H), 7.89 (d, 1H), 7.78 (t, 1H), 7.08 (d, 1H), 2.48(s, 3H); Anal. calc'd for C₂₀H₁₇N₄O₃F₃: C, 48.74; H, 3.33; N, 10.20 7/5TFA. Found: C, 48.74; H, 3.59; N, 10.11.

EXAMPLE 1956-(aminoiminomethyl)-N-(3,4,5-trimethoxyphenyl)-2-naphthalenecarboxamide,monohydrochloride EXAMPLE 195A

The above product was prepared in the manner of Example 8A using3,4,5-trimethoxyaniline.

MS (APCI) m/z (M+H)⁺ 363.

EXAMPLE 195B6-(aminoiminomethyl)-N-(3,4,5-trimethoxyphenyl)-2-naphthalenecarboxamide,monohydrochloride

The above was prepared as described in Example 1B.

MS (CI) m/z (M+H)⁺ 380; ¹H-NMR (300 MHz, d₆-DMSO) δ 10.54 (s, 1H), 9.61(s, 2H), 9.34 (s, 2H), 8.72 (s, 1H), 8.59 (s, 1H), 8.33-8.15 (m, 3H),7.91 (dd, 1H), 7.30 (s, 2H), 3.80 (s, 9H); Anal. calc'd for C₂₁H₂₂N₃O₄Cl63/10 HCl: C, 39.09; H, 4.42; N, 6.51. Found: C, 38.94; H, 4.60; N,7.61.

EXAMPLE 1966-(aminoiminomethyl)-N-(3-methyl-2-pyridinyl)-2-naphthalenecarboxamide,bis(trifluoroacetate)(salt) EXAMPLE 196A

Using the procedure described for Example 184A and substituting2-amino-3-picolene for 4-aminobenzamide, the desired compound wasobtained.

MS (DCI) m/z 288 (M+H)⁺.

EXAMPLE 196B6-(aminoiminomethyl)-N-(3-methyl-2-pyridinyl)-2-naphthalenecarboxamide,bis(trifluoroacetate)(salt)

Using the procedure described in Example 1B and the product obtained inExample 196A, the desired compound was obtained.

MS (DCI) m/z 305 (M+H)⁺; ¹H NMR (300 MHz, DMSO) δ 10.85 (s, 1H), 9.52(s, 2H), 9.22 (s, 2H), 8.76 (s, 1H), 8.56 (s, 1H), 8.35 (dd, 1H, J=4.41,1.10), 8.32 (d, 1H, J=8.80), 8.22 (m, 2H), 7.90 (dd, 1H, J=8.83, 1.84),7.80 (dd, 1H, J=7.73, 1.11), 7.31 (dd, 1H, J=7.72, 4.78), 2.26 (s, 1H);Anal. calc'd for C₂₂H₁₈F₆N₄O₃.0.75 H₂O: C, 48.40; H, 3.60; N. 10.26.Found: C, 48.81; H, 3.66; N, 10.43.

EXAMPLE 1976-(aminoiminomethyl)-N-(5-bromo-2-thiazolyll)-2-naphthalenecarboxamide,mono(trifluoroacetate)(salt) EXAMPLE 197A

Using the procedure described for Example 184A and substituting2-amino-5-bromothiazole for 4-aminobenzamide, the desired compound wasobtained.

MS (DCI) m/z 358 (M+H)⁺.

EXAMPLE 197B6-(aminoiminomethyl)-N-(5-bromo-2-thiazolyll)-2-naphthalenecarboxamide,mono(trifluoroacetate)(salt)

Using the procedure described in Example 1B and the product obtained inExample 197A, the desired compound was obtained.

MS (ESI+) m/z 375 (M+H)⁺; ¹H NMR (300 MHz, DMSO) δ 10.85 (s, 1H), 9.55(s, 2H), 9.24 (s, 2H), 8.87 (s, 1H), 8.87 (s, 1H), 8.57 (d, 1H, J=1.69),8.31 (d, 1H, J=8.47), 8.25 (d, 2H, J=1.01), 7.92 (dd, 1H, J=8.48, 2.04),7.71 (s, 1H); Anal. calc'd for C₁₇H₁₂BrF₃SN₄O₃.1.25 H₂O.0.25 TFA: C,38.90; H, 2.75; N, 10.37. Found: C, 38.97; H, 3.24; N, 10.66.

EXAMPLE 1986-(aminoiminomethyl)-N-(5-methyl-2-pyridinyl)-2-naphthalenecarboxamide,mono(trifluoroacetate)(salt) EXAMPLE 198A

Using the procedure described for Example 184A and substituting2-amino-5-picolene for 4-aminobenzamide, the desired compound wasobtained.

MS (ESI+) m/z 288 (M+H)⁺.

EXAMPLE 198B6-(aminoiminomethyl)-N-(5-methyl-2-pyridinyl)-2-naphthalenecarboxamide,mono(trifluoroacetate)(salt)

Using the procedure described in Example 1B and the product obtained inExample 198A, the desired compound was obtained.

MS (DCI) m/z 305 (M+H)⁺; ¹H NMR (300 MHz, DMSO) δ 11.01 (s, 1H), 9.50(s, 2H), 9.16 (s, 2H), 8.79 (s, 1H), 8.54 (s, 1H), 8.30 (d, 1H, J=9.19),8.27 (d, 1H, J=1.47), 8.20 (s, 2H), 8.15 (d, 1H, J=8.83), 7.89 (dd, 1H,J=8.46, 1.48), 7.72 (dd, 1H, J=8.46, 1.84), 2.31 (s, 3H); Anal. calc'dfor C₂₀H₁₇F₃N₄O₃.0.25 H₂O.0.2 TFA: C, 54.98; H, 4.00; N, 12.57. Found:C, 54.99; H, 3.59; N, 12.43.

EXAMPLE 1996-(aminoiminomethyl)-N-(4-methyl-2-thiazolyl)-2-naphthalenecarboxamide,mono(trifluoroacetate)(salt) EXAMPLE 199A

Using the procedure described for Example 184A and substituting2-amino-5-methyl benzothiazole for 4-aminobenzamide, the desiredcompound was obtained.

MS (ESI−) m/z 293 (M+H)⁻.

EXAMPLE 199B6-(aminoiminomethyl)-N-(4-methyl-2-thiazolyl)-2-naphthalenecarboxamide,mono(trifluoroacetate)(salt)

Using the procedure described in Example 1B and the product obtained inExample 199A, the desired compound was obtained.

MS (ESI+) m/z 311 (M+H)⁺; ¹H NMR (300 MHz, DMSO) δ 9.51 (s, 2H), 9.25(s, 2H), 8.86 (s, 1H), 8.55 (s, 1H), 8.30 (d, 1H, J=8.48), 8.25 (d, 1H,J=2.03), 7.91 (dd, 1H, J=8.48, 1.70), 6.87 (s, 1H), 2.34 (s, 3H); Anal.calc'd for C₁₈H₁₅F₃N₄SO₃.0.5 TFA: C, 47.40; H, 3.25; N, 11.64. Found: C,47.90; H, 3.36; N, 11.71.

EXAMPLE 2006-(aminoiminomethyl)-4-[5-(ethylthio)-3-furanyl]-N-phenyl-2-naphthalenecarboxamide,monohydrochloride EXAMPLE 200A

The desired compound was prepared from 2-trimethylsilyl-3-bromofuran anddiethyldisulfide by the procedure of Example 154A.

MS (DCI/NH₃) m/z 279, 281 (M+H)⁺.

EXAMPLE 200B

A solution of the product from Example 200A (8.60 g, 30.8 mmol) in THF(20 mL) and a 1 M solution of TBAF (61.6 mL) was stirred for 24 hours.The reaction was condensed and chromatographed on SiO₂ using hexanes aseluent, to yield 3.32 g (52%) of 2-ethylthio-4-bromofuran. The desiredcompound was prepared from this material by the procedure of Example57A.

MS (DCI/NH₃) m/z 127 (M−B (OH)₂)⁺.

EXAMPLE 200C

The desired compound was prepared from the product from Example 200B andthe product from Example 152C by the procedure of Example 57B.

MS (DCI/NH₃) m/z 416 (M+NH₄)⁺.

EXAMPLE 200D6-(aminoiminomethyl)-4-[5-(ethylthio)-3-furanyl]-N-phenyl-2-naphthalenecarboxamide,monohydrochloride

The desired compound was prepared from Example 200C and the procedure ofExample 144C.

MS (DCI/NH₃) m/z 416 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆) δ 1.30 (t, 3H),2.92 (q, 2H), 7.15 (t, 1H), 7.34 (s, 1H), 7.40 (t, 2H), 7.83 (d, 2H),7.92 (dd, 1H), 8.20 (d, 1H), 8.40 (d, 1H), 8.47 (s, 1H), 8.60 (s, 1H),8.69 (s, 1H), 9.21 (br s, 2H), 9.58 (br s, 2H), 10.61 (s, 1H); Anal.calc'd for C₂₄H₂₁N₃SO₂.1.5 HCl: C, 61.31; H, 4.82; N, 8.94. Found: C,61.39; H, 4.89; N, 9.03.

EXAMPLE 2016-(aminoiminomethyl)-4-[5-(propylthio)-3-furanyl]-N-phenyl-2-naphthalenecarboxamide,monohydrochloride EXAMPLE 201A

The desired compound was prepared from 2-trimethylsilyl-3-bromofuran anddipropyldisulfide by the procedure of Example 154A.

MS (DCI/NH₃) m/z 293, 295 (M+H)⁺.

EXAMPLE 201B

The desired compound was prepared from the product from Example 201A bythe procedure of 154B.

MS (DCI/NH₃) m/z 432 (M+H)⁺.

EXAMPLE 201C

The desired compound was prepared from the product from Example 201B andthe product from Example 152C by the procedure of Example 154C.

MS (DCI/NH₃) m/z 430 (M+NH₄)⁺.

EXAMPLE 201D6-(aminoiminomethyl)-4-[5-(propylthio)-3-furanyl]-N-phenyl-2-naphthalenecarboxamide,monohydrochloride

The desired compound was prepared from Example 201C and the procedure ofExample 144C.

MS (DCI/NH₃) m/z 430 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆) δ 1.1 (t, 3H),1.66 (qt, 2H), 2.89 (t, 2H), 7.15 (t, 1H), 7.34 (s, 1H), 7.40 (t, 2H),7.84 (d, 2H), 7.92 (dd, 1H), 8.20 (d, 1H), 8.40 (d, 1H), 8.47 (s, 1H),8.60 (s, 1H), 8.69 (s, 1H), 9.22 (br s, 2H), 9.58 (br s, 2H), 10.61 (s,1H); Anal. calc'd for C₂₅H₂₃N₃SO₂.1.25 HCl: C, 63.20; H, 5.14; N, 8.84.Found: C, 63.24; H, 5.16; N, 8.93.

EXAMPLE 2026-(aminoiminomethyl)-N-(6-quinolinyl)-2-naphthalenecarboxamide,bis(trifluoroacetate)(salt) EXAMPLE 202A

To a solution of the acid chloride, Example 8B, (331 mg, 1.5 mmol) inTHF (15 mL), at room temperature, was added propylene oxide (10 mL),DMAP (5 mg), a drop of triethylamine and finally 6-aminoquinoline (288mg, 2.0 mmol). After 4 hours at room temperature, added ethyl acetate(10 mL) and ether (20 mL) and filtered the off-white solid product.Yield 357 mg (72%).

MS (DCI/NH₃) m/z 324 (M+H)⁺.

EXAMPLE 202B6-(aminoiminomethyl)-N-(6-quinolinyl)-2-naphthalenecarboxamide,bis(trifluoroacetate)(salt)

The desired compound was prepared as described in Example 1B.

MS (ESI⁺) m/z 341 (M+H)⁺, (ESI⁻) 339 (M−1)⁻; ¹H NMR (300 MHz, DMSO-d₆) δ10.98 (s, 1H), 9.53 (s, 2H), 9.25 (s, 2H), 8.93-8.91 (m, 1H), 8.77 (s,1H), 8.67 (d, J=1.8 Hz, 1H), 8.58 (s, 1H), 8.53 (d, J=8.5 Hz, 1H),8.37-8.09 (m, 5H), 7.93 (dd, J1=8.5 Hz, J2=1.8 Hz, 1H), 7.65-7.62 (m,1H); Anal. calc'd for C₂₁H₁₆N₄O.2TFA: C, 52.83; H, 3.19; N, 9.86. Found:C, 52.62; H, 2.94; N, 9.74.

EXAMPLE 2036-(aminoiminomethyl)-N-(1H-indazol-6-yl)-2-naphthalenecarboxamide,bis(trifluoroacetate)(salt) EXAMPLE 203A

The desired compound was prepared as described for Example 202A butsubstituting 6-aminoquinoline for 6-aminoindazole to provide 285 mg ofthe desired compound.

MS: ESI+: 313 (M+1); ESI−311 (M−1).

EXAMPLE 203B6-(aminoiminomethyl)-N-(1H-indazol-6-yl)-2-naphthalenecarboxamide,bis(trifluoroacetate)(salt)

To a suspension of the ammonium chloride (140 mg, 2.6 mmol) in Toluene(2 mL) at 0° C. was slowly added a solution of 2 N trimethylaluminum intoluene (871 μL, 1.74 mmol). After 5 minute the reaction mixture wasallowed to warm to room temperature for 30 minutes. To the solution ofthe aluminium reagent at room temperature was added the nitrile, Example203A from section (a) and the reaction mixture was heated to 100° C. for48 hours. The reaction mixture was cooled down then was poured into asuspension of silica in chloroform and stirred for an hour. The silicawas filtered then washed with methanol. The solvent was concentrated andpurified by medium pressure liquid chromatography on a 30 cm×2 cm C-18column (40 micron, J. T Baker) with UV detection at 250 nM with solventmixtures in a gradient ranging from 90% A (0.1% aq TFA)/10% B (methanol)to 10% A/90% B over 160 minutes at a flow rate of 5 mL/min (fractionswere collected every 2 minutes for 100 min, to provide 42 mg of thedesired compound.

MS (ESI⁺) m/z 330 (M+H)⁺, (ESI⁻) 328 (M−1)⁻; ¹H NMR (300 MHz, DMSO-d₆) δ10.65 (s, 1H), 9.47 (m, 4H), 8.65 (s, 2H), 8.50 (s, 2H), 8.25-8.23 (m,2H), 8.17-8.10 (m, 2H), 7.94 (s, 1H), 7.86-7.84 (dd, J1=8.8Hz, J2=1.6 Hz1H), 7.66 (d, J=8.5 Hz, 1H), 7.37 (d, J=8.4 Hz, 1H); Anal. calc'd forC₁₉H₁₅N₅ O.2 TFA: C, 49.56; H, 3.07; N, 12.56. Found: C, 49.68; H, 3.10;N, 12.47.

EXAMPLE 2046-(aminoiminomethyl)-N-(1H-indazol-5-yl)-2-naphthalenecarboxamide,bis(trifluoroacetate)(salt) EXAMPLE 204A

The desired compound was prepared as described for Example 202A butsubstituting 6-aminoquinoline for 5-aminoindazole to provide 362 mg ofthe desired compound.

MS: ESI+: 313 (M+1); ESI−311 (M−1).

EXAMPLE 204B6-(aminoiminomethyl)-N-(1H-indazol-5-yl)-2-naphthalenecarboxamide,bis(trifluoroacetate)(salt)

The desired compound was prepared as described for Example 203B toprovide 55 mg of the desired compound.

MS (ESI⁺) m/z 330 (M+H)⁺, (ESI⁻) 328 (M−1); ¹H NMR (300 MHz, DMSO-d₆) δ13.06 (s, 1H), 10.58 (s, 1H), 9.51 (s, 2H), 9.15 (s, 2H), 8.71 (d, j=1.9Hz, 1H), 8.56 (d, j=1.9 Hz, 1H), 8.34-8.17 (m, 4H), 8.10 (s, 1H), 7.90(dd, J1=8.5 Hz, J2=1.7 Hz, 1H), 7.63 (dd, J1=8.9 Hz, J2=1.7 Hz, 1H),7.56 (d, J=8.8 Hz, 1H); Anal. calc'd for C₁₉H₁₅N₅ O.TFA. 1.75 H₂O: C,53.11; H, 4.14; N, 14.75. Found: C, 53.20; H, 3.99; N, 14.42.

EXAMPLE 2056-(aminoiminomethyl)-N-(1H-indol-5-yl)-2-naphthalenecarboxamide,mono(trifluoroacetate)(salt) EXAMPLE 205A

The desired compound was prepared as described for Example 202A butsubstituting 6-aminoquinoline for 6-aminoindole to provide 744 mg of thedesired compound.

MS: (ESI)+: 329 (M+1)+and (ESI)−: 327 (M−1)−.

EXAMPLE 205B6-(aminoiminomethyl)-N-(1H-indol-5-yl)-2-naphthalenecarboxamide,mono(trfluoroacetate)(salt)

The desired compound was prepared as described for Example 203B toprovide 90 mg of the desired compound.

MS (ESI⁺) m/z 329 (M+H)⁺, (ESI⁻) 327 (M−1)⁻; ¹H NMR (300 MHz, DMSO-d₆) δ11.09 (s, 1H), 10.40 (s, 1H), 9.51 (s, 2H), 9.15 (s, 2H), 8.71 (s, 1H),8.55 (s, 1H), 8.32 (d, J=8.4 Hz, 1H), 8.26-8.17 (m, 2H), 8.05 (d, J=2.6Hz, 1H), 7.90 (dd, J1=8.4 Hz, J2=1.8 Hz, 1H), 7.46-7.35 (m, 3H),6.45-6.43 (m, 1H); Anal. calc'd for C₂₀H₁₆N₄ O.TFA: C, 59.73; H, 3.87;N, 12.66. Found: C, 59.27; H, 4.17; N, 12.74.

EXAMPLE 206 7-[2-(4-morpholinyl)ethoxy]-2-naphthalenecarboximidamide,bis(trifluoroacetate)(salt) EXAMPLE 206A

The nitrile was prepared as described in Example 119A using2-chloroethylmorpholine.

MS (DCI (NH₃)) m/z 283 (M+H)⁺.

EXAMPLE 206B 7-[2-(4-morpholinyl)ethoxy]-2-naphthalenecarboximidamide,bis(trifluoroacetate)(salt)

The desired compound was prepared as described in Example 119B, as anoff-white solid (50% yield).

MS (DCI (NH₃)) m/z 300 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆) δ 3.500 (br m,4H), 3.700 (br m, 2H), 3.990 (br m, 4H), 4.490 (br m, 2H), 7.435 (dd,1H), 7.530 (d, 1H), 7.680 (dd, 1H), 8.035 (d, 1H), 8.100 (d, 1H), 8.345(d 1H), 9.165 (br s, 2H), 9.420 (br s, 2H); Anal. calc'd forC₁₇H₂₁N₃O₂.(C₂HO₂F₃)_(2.15): C, 46.98; H, 4.29; N, 7.72. Found: C,47.00; H, 4.32; N, 7.77.

EXAMPLE 2076-(aminoiminomethyl)-N-phenyl-4-(2-pyrolidinyl)-2-naphthalenecarboxamide,mono(trifluoroacetate)(salt) EXAMPLE 207A

The desired compound was prepared from the product from Example 152A, bythe procedure of Example 68A.

MS (DCI/NH₃) m/z 281 (M+H)⁺.

EXAMPLE 207B

The desired compound was prepared from the product from Example 207A bythe procedure of Example 152B.

MS (DCI/NH₃) m/z 267 (M+H)⁺.

EXAMPLE 207C

A solution of the product from Example 207B (220 mg, 0.826 mmol),diisopropylethyl amine (0.288 mL, 1.65 mmol), andO-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (314 mg, 0.826 mmol) in DMF (10 mL) was stirred for30 minutes at 0° C. Aniline (0.083 mL, 0.909 mmol) was added, and thereaction was stirred at room temperature for 4 hours. The reaction waspoured into saturated aqueous Na₂CO₃ solution, and extracted with3×ethyl acetate. The combined extracts were washed with water and brine,dried over Na₂SO₄, and condensed. The crude material was recrystallizedfrom ethanol/hexanes to yield 212 mg (75%) of the desired compound.

MS (DCI/NH₃) m/z 342 (M+H)⁺.

EXAMPLE 207D6-(aminoiminomethyl)-N-phenyl-4-(2-pyrrolidinyl)-2-naphthalenecarboxamide,mono(trifluoroacetate)(salt)

The desired compound was prepared from Example 207C and the procedure ofExample 1B.

MS (DCI/NH₃) m/z 359 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆) δ 2.02 (t, 4H),3.55 (t, 4H), 7.13 (t, 1H), 7.38 (t, 2H), 7.41 (s, 1H), 7.80 (m, 3H),8.08 (s, 1H), 8.18 (d, 1H), 8.67 (s, 1H), 9.10 (br s, 2H), 9.43 (br s,2H), 10.41 (br s, 1H); Anal. calc'd for C₂₂H₂₂N₄O.1.0 C₂HF₃O₂: C, 61.01;H, 4.91; N, 11.86. Found: C, 60.47; H, 5.36; N, 7.39.

EXAMPLE 2086-(aminoiminomethyl)-N-(5-pyrimidinyl)-2-naphthalenecarboxamide,mono(trifluoroacetate)(salt) EXAMPLE 208A

The above product was prepared in the manner of Example 8A using5-aminopyrimidne.

MS (APCI) m/z (M+H)⁺ 275.

EXAMPLE 208B6-(aminoiminomethyl)-N-(5-pyrimidinyl)-2-naphthalenecarboxamide,mono(trifluoroacetate)(salt)

The above was prepared as described in Example 1B.

MS (CI) m/z (M+H)⁺ 292; ¹H-NMR (300 MHz, DMSO-d₆) δ 10.99 (s, 1H), 9.52(s, 2H), 9.27 (s, 2H), 9.24 (s, 2H), 8.98 (s, 1H), 8.76 (s, 1H), 8.58(s, 1H), 8.36-8.18 (m, 3H), 7.92 (dd, J=1.5, 8.4 Hz, 1H); Anal. calc'dfor C₁₈H₁₄N₅O₃F₃ 7/10 TFA: C, 47.97; H, 3.05; N, 14.40. Found: C, 47.78;H, 3.05; N, 14.67.

EXAMPLE 2096-(aminoiminomethyl)-N-(3-pyridazinyl)-2-naphthalenecarboxamide,mono(trifluoroacetate)(salt) EXAMPLE 209A

3-Amino-6-chloropyridazine (1.05 g, 8.2 mmol) was dissolved in 10 mLmethanol with 2 mL ammonia/methanol. Palladium/carbon (200 mg, 10%) wasadded and stirred under 1 atm hydrogen for 4 hours. The reaction wasfiltered, concentrated, and used without further purification.

MS (CI) m/z (M+H)⁺ 96.

EXAMPLE 209B

The above product was prepared in the manner of Example 12 using theproduct from Example 209A.

MS (APCI) m/z (M+H)⁺ 275.

EXAMPLE 209C6-(aminoiminomethyl)-N-(3-pyridazinyl)-2-naphthalenecarboxamide,mono(trifluoroacetate)(salt)

The above was prepared from Example 209B as described in Example 1B.

MS (CI) m/z (M+H)⁺ 292; ¹H-NMR (300 MHz, d₆-DMSO) δ 11.72 (s, 1H), 9.51(s, 2H), 9.22 (s, 2H), 9.06 (m, 1H), 8.86 (s, 1H), 8.56 (s, 1H), 8.45(d, 1H), 8.31 (d, 1H), 8.23 (s, 2H), 7.90 (dd, 1H), 7.78 (dd, 1H) Anal.calc'd for C₁₈H₁₄N₅O₃F₃ 1/2 TFA: C, 49.29; H, 3.16; N, 14.73. Found: C,49.56; H, 3.23; N, 14.73.

EXAMPLE 2106-(aminoiminomethyl)-N-(5-bromo-2-pyridinyl)-2-naphthalenecarboxamide,mono(trifluoroacetate)(salt) EXAMPLE 210A

Using the product obtained in Example 8E, 2-amino-5-bromopyridine, andthe procedure described for Example 8G the desired compound wasobtained.

MS (APCI+) m/z 352 (M+H)⁺.

EXAMPLE 210B6-(aminoiminomethyl)-N-(5-bromo-2-pyridinyl)-2-naphthalenecarboxamide,mono(trifluoroacetate)(salt)

Using the procedure described in Example 1B and the product obtained inExample 210A, the desired compound was obtained.

MS (DCI) m/z 369 (M+H)⁺; ¹H NMR (300 MHz, DMSO) δ 11.30 (s, 1H), 9.51(s, 2H), 9.17 (s, 2H), 8.80 (s, 1H), 8.57 (d, 1H, J=2.57), 8.55 (s, 1H),8.31 (d, 1H, J=8.45), 8.26 (d, 1H, J=8.82), 8.19-8.24 (m, 2H, ), 8.14(dd, 1H, J=2.57, 9.19), 7.90 (dd, 1H, J=1.83, 8.82; Anal. calc'd forC₁₉H₁₄BrF₃N₄O₃: C, 47.22; H, 2.92; N, 11.59. Found: C, 47.60; H, 3.01;N, 11.30.

EXAMPLE 2116-(aminoiminomethyl)-N-3-(1-methylethoxy)phenyl]-2-naphthalenecarboxamide,mono(trifluoroacetate)(salt) EXAMPLE 211A

The above product was prepared in the manner of Example 12 using3-isopropoxyaniline.

MS (APCI) m/z (M+H)⁺ 331.

EXAMPLE 211B6-(aminoiminomethyl)-N-[3-(1-methylethoxy)phenyl]-2-naphthalenecarboxamide,mono(trifluoroacetate)(salt)

The above was prepared from Example 211A using method 1B.

MS (CI) m/z (M+H)⁺ 348; ¹H-NMR (300 MHz, d₆-DMSO) δ 10.50 (s, 1H), 9.50(s, 2H), 9.22 (s, 2H), 8.67 (s, 1H), 8.56 (s, 1H), 8.31 (d, 1H),8.25-8.13 (m, 2H), 7.90 (dd, 1H), 7.51 (m, 1H), 7.36 (m, 1H), 7.26 (t,1H), 6.68 (dd, 1H), 4.59 (m, 1H), 1.30 (d, 6H); Anal. calc'd forC₂₃H₂₂N₃O₄F₃ 1/5 TFA: C, 57.96; H, 4.61; N, 8.66. Found: C, 57.99; H,4.90; N, 8.68.

EXAMPLE 212 2-[[6-(aminoiminomethyl)-2-naphthalenyl]oxy]acetic acid,mono(trifluoroacetate)(salt)

The product from Example 185C (140 mg, 0.542 mmol) was dissolved inmethanol (11 mL). To this was added a solution of lithium hydroxide(68.2 mg, 1.626 mmol) in water (3 mL) and the resulting mixture wasstirred at room temperature under an inert atmosphere for 18 hours. Thereaction was evaporated and the residue purified by reverse phasechromatography to yield the desired compound (102 mg, 52%).

MS (DCI (NH₃)) m/z 245 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆) δ 4.875 (s,2H), 7.420 (s, 1H), 7.435 (dd, 1H), 7.660 (dd, 1H), 8.015 (d, 1H), 8.100(d, 1H), 8.340 (d. 1H), 9.125 (br s, 1H), 9.420 (br s, 1H; Anal. calc'dfor C₁₃H₁₂N₂O₃.(C₂HO₂F₃)_(1.30): C, 47.74; H, 3.42; N, 7.14. Found: C,47.93; H, 3.36; N, 7.17.

EXAMPLE 213 Methyl4-[6-(aminoiminomethyl)-2-naphthalenyl]oxy]methyl]benzoate,mono(trifluoroacetate)(salt) EXAMPLE 213A

The resulting product from Exanple 185A was treated with methyl4-(bromomethyl)benzoate in an analogous manner as described in Example119B.

MS (DCI (NH₃)) m/z 335 (M+NH₄)⁺.

EXAMPLE 213B Methyl4-[6-(aminoiminomethyl)-2-naphthalenyl]oxy]methyl]benzoate,mono(trifluoroacetate)(salt)

The resulting product from Example 213A (250 mg, 0.788 mmol) was treatedin an analogous manner as described in Example 119C to yield the desiredcompound (130 mg, 79%).

MS (DCI (NH₃)) m/z 335 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆) δ 3.870 (s,3H), 5.400 (s, 2H), 7.500 (dd, 1H), 7.540 (d, 1H), 7.619 (dd, 1H), 7.620(d, 2H), 8.025 (d, 2H), 8.026 (d, 1H), 8.090 (d, 1H), 8.410 (d, 1H),9.260 (v br s, 3H); Anal. calc'd for C₁₄H₁₄N₂O₃.C₂HO₂F₃.H₂O 0.70: C,57.32; H, 4.46; N, 6.08. Found: C, 57.33; H, 4.70; N, 5.95.

EXAMPLE 2146-(aminoiminomethyl)-N-(1H-imidazolyl)-2-naphthalenecarboxamide,bis(trifluoroacetate)(salt) EXAMPLE 214A

Using the product obtained in Example 8E, 2-aminoimidazole, and theprocedure described for Example 8G the desired compound was obtained.

MS (ESI−) m/z 261 (M+H)⁻.

EXAMPLE 214B

Using the procedure described in Example 1B and the product obtained inExample 214A, the desired compound was obtained.

MS (ESI+) m/z 280 (M+H)⁺; ¹H NMR (300 MHz, DMSO) δ 9.50 (s, 2H), 9.16(s, 2H), 8.78 (s, 1H), 8.53 (s, 1H), 8.26-8.31 (m, 2H), 8.20 (d, 1H,J=8.46), 7.88 (dd, 1H, J=1.84, 8.83), 6.95 (s, 2H); Anal. calc'd forC₁₇H₁₄F₃N₅O₃.0.2 TFA.H₂O: C, 48.14; H, 3.76; N, 16.13. Found: C, 48.54;H, 3.40; N, 16.02.

EXAMPLE 2156-[2-[4-(hydroxymethyl)phenyl]1-cyclopropyl]-2-naphthalenecarboximidamide,mono(trifluoroacetate)(salt) EXAMPLE 215A

The material prepared as described in Example 104 (210 mg, 0.52 mmol) isdissolved in THF (6 mL) and added dropwise to 10 mL diazomethane cooledto 0° C. then added Pd (OAc)₂ (9.8 mg). Vigorous bubbling occurs for 5minutes. the resulting black slurry is stirred 20 min, filtered andsolvent removed under vacuum leaving 0.1 g clear oil.

MS (DCI/NH₃): m/z (M+NH₄ ⁺): 316.

EXAMPLE 215B6-[2-[4-(hydroxymethyl)phenyl]-1-cyclopropyl]-2-naphthalenecarboximidamide,mono(trifluoroacetate)(salt)

The desired compound is prepared as described in Example 1, purified byreverse phase chromatography to give 19.9 mg of white solid.

MS (DCI/NH₃) m/z (M+H)⁺ 316; ¹H-NMR (300 MHz, DMSO-d₆) δ 9.41 (s, 2H),9.16 (s, 2H), 8.46 (s, 1H), 8.08 (d, 2H), 8.03 (d, 1H), 7.85 (s, 1H),7.75 (dd, 1H), 7.58 (dd, 1H), 7.3-7.1 (m, 4H), 4.49 (s, 2H), 2.38-2.48(m, 2H), 1.61-1.70 (m, 2H); Anal. calc'd for C₂₃H₂₁N₂O₂F₃ 1 H₂O: C,62.10; H, 4.80; N, 6.29. Found: C, 62.00; H, 4,75; N, 6.25.

EXAMPLE 216N-(ethoxycarbonyl)-6-(2-phenyl-1-cyclopropyl)-2-naphthalenecarboximidamide

The sample described in Example 97 (130 mg, 0.45 mmol) is dissolved inDMF (3 mL) cooled to 0° C. and treated with triethylamine (0.01 mL) andethyl chloroformate (0.05 mL). The resulting solution is stirred threedays at room temperature then diluted with 100 mL ethyl acetate washedwith distilled water (20 mL), dried over anhydrous sodium sulfate,filtered and solvent removed under vacuum leaving a clear oil. The oilis purified by silica gel chromatography eluthing with 2:1 hexanes/ethylacetate, lyophilized and the desired compound is isolated as a whitepowder (55 mg).

MS (DCI/NH₃) m/z (M+H)⁺ 359; ¹H-NMR (300 MHz, DMSO-d₆) δ 9.21 (s, 2H),8.46 (s, 1H), 7.83 (d, 2H), 7.62 (s, 1H), 7.58 (dd, 1H), 7.34 (dd, 1H),7.35-7.29 (m, 3H), 7.25-7.17 (m, 2H) 4.1 (q, 2H), 2.38-2.28 (m, 2H),1.61 (t, 2H), 1.25 (t, 3H); Anal. calc'd for C₂₃H₂₂N₂O₂ C, 77.07; H,6.19; N, 7.82. Found: C, 76.63; H, 6.05; N, 7.45.

EXAMPLE 217

6-(aminoiminomethyl)-N-(2-methyl-6-quinolinyl)-2-naphthalenecarboxamide,bis(trifluoroacetate)(salt)

The desired compound is prepared in a similar manner as described inExample 8E and 144C.

MS m/z: 355 (M+H)⁺; ¹H NMR (DMSO, 300 MHz): 10.95 (s, 1H), 9.51 (s, 2H),9.14 (s, 2H), 8.75 (s, 1H), 8.65 (s, 1H), 8.57 (s, 1H), 8.35 (dd, 1H,J1=J2=8.5 Hz), 8.28 (dd, 1H, J1=J2=8.5 Hz), 8.19 (dd, 1H, J1=J2=8.8 Hz),8.15 (dd, 1H, J1=J2=8.3 Hz), 8.04 (dd, 1H, J1=J2=8.8 Hz), 7.91 (dd, 1H,J1=8.4 Hz, J2=8.8 Hz), 7.60 (dd, 1H, J1=J2=8.1 Hz). 5.99 (S, 3H); Anal.calc'd for C₂₂H₁₈N₄O.2.25 C₂F₃O₂H.2 H₂O: C, 49.20; H, 3.78; N, 8.66; F,19.82. Found: C, 49.02; H, 3.36; N, 8.66.

EXAMPLE 2186-(aminoiminomethyl)-N-(3-propoxyphenyl)-2-naphthalenecarboxamide,mono(trifluoroacetate)(salt) EXAMPLE 218A

3-Aminophenol (1 g, 7.2 mmol), triphenylphosphine (2.25 g, 8.6 mmol),and 1-propanol (0.517 g, 8.6 mmol) were dissolved in 25 mL anhydrousTHF. Diethylazodicarboxylate (1.5 g, 8.6 mmol) was added dropwise over 1minute. The solution was allowed to stir 15 minutes and poured slowlyinto hexanes while stirring. Filtration through silica gel/celiteafforded the product as a viscous yellow oil.

MS (APCI) m/z (M+H)⁺ 152.

EXAMPLE 218B

The above product was prepared in the manner of Example 12 using theproduct from Example 218A.

MS (APCI) m/z (M+H)⁺ 331.

EXAMPLE 218C6-(aminoiminomethyl)-N-(3-propoxyphenyl)-2-naphthalenecarboxamide,mono(trifluoroacetate)(salt)

The above was prepared from Example 218 as described in Example 1B.

MS (CI) m/z (M+H)⁺ 348; ¹H-NMR (300 MHz, d₆-DMSO) δ 10.51 (s, 1H), 9.50(s, 2H), 9.18 (s, 2H), 8.68 (s, 1H), 8.55 (s, 1H), 8.32 (d, 1H),8.25-8.13 (m, 2H), 7.90 (dd, 1H), 7.52-7.33 (m, 2H), 7.27 (t, 1H), 6.73(dd, 1H), 3.94 (t, 2H), 1.75 m, 2H), 1.00 (t, 3H); Anal. calc'd forC₂₃H₂₂N₃O₄F₃: 1/20 TFA: C, 59.49; H, 4.77; N, 9.02. Found: C, 59.43; H,4.94; N, 9.10.

EXAMPLE 2196-(aminoiminomethyl)-N-[3-(1-ethylpropoxy)phenyl]-2-naphthalenecarboxamide,mono(trifluoroacetate)(salt) EXAMPLE 219A

The above product was prepared in the manner of Example 218A using3-pentanol.

MS (APCI) m/z (M+H)⁺ 180.

EXAMPLE 219B

The above product was prepared in the manner of Example 12 using theproduct from Example 219A.

MS (APCI) m/z (M+H)⁺ 359.

EXAMPLE 219C6-(aminoiminomethyl)-N-[3-(1-ethylpropoxy)phenyl]yl-2-naphthalenecarboxamide,mono(trifluoroacetate)(salt)

The above was prepared from Example 219B as described in Example 1B.

MS (CI) m/z (M+H)⁺ 376; ¹H-NMR (300 MHz, d₆-DMSO) δ 10.47 (s, 1H), 9.49(s, 2H), 9.14 (s, 2H), 8.67 (s, 1H), 8.55 (s, 1H), 8.31 (d, 1H),8.25-8.16 (m, 2H), 7.90 (dd, 1H), 7.51 (s, 1H), 7.38 (m, 1H), 7.26 (t,1H), 6.72 (dd, 1H), 4.18 (m, 1H), 1.65 (m, 4H), 0.93 (t, 6H); Anal.calc'd for C₂₅H₂₆N₃O₄F₃: C, 61.34; H, 5.35; N, 8.58. Found: C, 61.05; H,5.42; N, 8.22.

EXAMPLE 2206-(aminoiminomethyl)-N-[3-(cyclopentyloxy)phenyl]-2-naphthalenecarboxamide,mono(trifluoroacetate)(salt) EXAMPLE 220A

The above product was prepared in the manner of Example 218A usingcyclopentanol.

MS (APCI) m/z (M+H)⁺ 86.

EXAMPLE 220B

The above product was prepared in the manner of Example 12 using theproduct from Example 220A.

MS (APCI) m/z (M+H)⁺ 357.

EXAMPLE 220C6-(aminoiminomethyl)-N-[3-(cyclopentyloxy)phenyl]-2-naphthalenecarboxamide,mono(trifluoroacetate)(salt)

The above was prepared from Example 220B as described in Example 1B.

MS (CI) m/z (M+H)⁺ 374; ¹H-NMR (300 MHz, d₆-DMSO) δ 10.50 (s, 1H), 9.51(s, 2H), 9.30 (s, 2H), 8.68 (s, 1H), 8.56 (s, 1H), 8.32 (d, 1H),8.25-8.13 (m, 2H), 7.90 (dd, 1H), 7.49 (m, 1H), 7.38 (m, 1H), 7.26 (t,1H), 6.72 (dd, 1H), 4.79 (m, 1H), 1.96-1.08 (m, 8H). Anal. calc'd forC₂₅H₂₄N₃O₄F₃ 2/5 TFA: C, 60.68; H, 5.06; N, 8.49. Found: C, 60.68; H,5.33; N, 8.65.

EXAMPLE 2216-(aminoiminomethyl)-N-(3-phenoxyphenyl)-2-naphthalenecarboxamide,mono(trifluoroacetate)(salt) EXAMPLE 221A

The above product was prepared in the manner of Example 218A using3-phenoxyanline.

MS (APCI) m/z (M+H)⁺ 365.

EXAMPLE 221B6-(aminoiminomethyl)-N-(3-phenoxyphenyl)-2-naphthalenecarboxamide,mono(trifluoroacetate)(salt)

The above was prepared from Example 221A as described in Example 1B.

¹H-NMR (300 MHz, d₆-DMSO) δ 10.61 (s, 1H), 9.50 (s, 2H), 9.20 (s, 2H),8.66 (s, 1H), 8.54 (s, 1H), 8.30 (d, 1H), 8.22 (d, 1H), 8.12 (dd, 1H),7.90 (dd, 1H), 7.64-7.57 (m, 2H), 7.46-7.37 (m, 3H), 7.17 (m, 1H), 7.06(m, 2H), 6.79 (dd, 1H), MS (CI) m/z (M+H)⁺ 382; Anal. calc'd forC₂₆H₂₀N₃O₄F₃: C, 63.03; H, 4.07; N, 8.48. Found: C, 62.87; H, 4.24; N,8.08.

EXAMPLE 2226-(aminoiminomethyl)-N-[3-(phenylmethoxy)phenyl]-2-naphthalenecarboxamide,mono(trifluoroacetate)(salt) EXAMPLE 222A

The above product was prepared in the manner of Example 218A using3-benzyloxyaniline.

MS (APCI) m/z (M+H)⁺ 379.

EXAMPLE 222B6-(aminoiminomethyl)-N-[3-(phenylmethoxy)phenyl]-2-naphthalenecarboxamide,mono(trifluoroacetate)(salt)

The above was prepared from Example 222A as described in 1B.

MS (CI) m/z (M+H)⁺ 396; ¹H-NMR (300 MHz, d₆-DMSO) δ 10.53 (s, 1H), 9.50(s, 2H), 9.22 (s, 2H), 8.68 (s, 1H), 8.55 (s, 1H), 8.31 (d, 1H), 8.23(d, 1H), 8.14 (dd, 1H), 7.90 (dd, 1H), 7.61-7.27 (m, 8H), 6.80 (dd, 1H),5.13 (s, 2H); Anal. calc'd for C₂₇H₂₂N₃O₄F₃: C, 63.65; H, 435; N, 8.25.Found: C, 63.48; H, 4.27; N, 8.07.

EXAMPLE 2236-(aminoiminomethyl)-N-(3-ethoxyphenyl)-2-naphthalenecarboxamide,mono(trifluoroacetate)(salt) EXAMPLE 223A

The above product was prepared in the manner of Example 218A using3-ethoxyaniline.

MS (APCI) m/z (M+H)⁺ 317.

EXAMPLE 223B6-(aminoiminomethyl)-N-(3-ethoxyphenyl)-2-naphthalenecarboxamide,mono(trifluoroacetate)(salt)

The above was prepared from Example 223A as described in Example 1B.

MS (CI) m/z (M+H)⁺ 334; ¹H-NMR (300 MHz, d₆-DMSO) δ 10.52 (s, 1H), 9.50(s, 2H), 9.24 (s, 2H), 8.68 (s, 1H), 8.55 (s, 1H), 8.32 (d, 1H),8.25-8.13 (m, 2H), 7.90 (dd, 1H), 7.51 (m, 1H), 7.38 (m, 1), 7.26 (t,1H), 6.72 (dd, 1H), 4.04 (q, 2H), 1.34 (t, 3H); Anal. calc'd forC₂₂H₂₀N₃O₄F₃: C, 59.06; H, 4.51; N, 9.39. Found: C, 58.69; H, 4.54; N,9.82.

EXAMPLE 2246-(aminoiminomethyl)-N-(4-nitrophenyl)-2-naphthalenecarboxamide,mono(trifluoroacetate)(salt) EXAMPLE 224A

The above product was prepared in the manner of Example 218A using4-nitroaniline.

MS (APCI) m/z (M+H)⁺ 318.

EXAMPLE 224B6-(aminoiminomethyl)-N-(4-nitrophenyl)-2-naphthalenecarboxamide,mono(trifluoroacetate)(salt)

The above was prepared from Example 224A as described in Example 1B.

MS (CI) m/z (M+H)⁺ 335; ¹H-NMR (300 MHz, d₆-DMSO) δ 11.15 (s, 1H), 9.55(s, 2H), 9.22 (s, 2H), 8.77 (s, 1H), 8.58 (s, 1H), 8.36-8.12 (m, 7H);Anal. calc'd for C₂₀H₁₅N₄O₅F₃ 1/10 TFA: C, 52.54; H, 3.29; N, 12.10.Found: C, 53.58; H, 3.37; N, 12.50.

EXAMPLE 2256-(aminoiminomethyl)-N-[3-(cyclobutylmethoxy)phenyl]-2-naphthalenecarboxamide,mono(trifluoroacetate)(salt) EXAMPLE 225A

The above product was prepared in the manner of Example 218A usingcyclobutylmethanol.

MS (APCI) m/z (M+H)⁺ 177.

EXAMPLE 225B

The above product was prepared in the manner of Example 225A using theproduct from Example 11

MS (APCI) m/z (M+H)⁺ 357.

EXAMPLE 225C6-(aminoiminomethyl)-N-[3-(cyclobutylmethoxy)phenyl]-2-naphthalenecarboxamide,mono(trifluoroacetate)(salt)

The above was prepared from Example 225B as described in Example 1B.

MS (CI) m/z (M+H)⁺ 374; ¹H-NMR (300 MHz, d₆-DMSO) δ 10.50 (s, 1H), 9.50(s, 2H), 9.20 (s, 2H), 8.68 (s, 1H), 8.55 (s, 1H), 8.32 (d, 1H),8.25-8.13 (m, 2H), 7.90 (dd, 1H), 7.51 (m, 1H), 7.38 (m, 1H), 7.26 (t,1H), 6.72 (dd, 1H), 3.95 (d, 2H), 2.11-1.81 (m, 7H); Anal. calc'd forC₂₅H₂₄N₃O₄F₃ 7/5 TFA: C, 59.09; H, 5.22; N, 8.27. Found: C, 59.02; H,5.20; N, 8.55.

EXAMPLE 2266-[amino(ethoxycarbonyl)imino]-N-[3-(1-methylethoxy)phenyl]-2-naphthalenecarboxamide

The above was prepared from Example 211A using method described inExample 216.

MS (CI) m/z (M+H)⁺ 420; ¹H-NMR (300 MHz, d₆-DMSO) δ 10.41 (s, 1H), 9.24(br, 2H), 8.67 (s, 1H), 8.59 (s, 1H), 8.12-7.96 (m, 4H), 7.47 (s, 1H),7.36 (m, 1H), 7.25 (t, 1H), 6.67 (dd, 1H), 4.58 (m, 1H), 4.11 (q, 2H),1.30 (m, 9H); Anal. calc'd for C₂₄H₂₅N₃O₄ 1/4 H₂O: C, 67.99; H, 6.06; N,9.91. Found: C, 67.99; H, 6.07; N, 9.64.

EXAMPLE 2276-(aminoiminomethyl)-4-[5-(ethylsulfonyl)-3-furanyl]-N-phenyl-2-naphthalenecarboxamide,monohydrochloride EXAMPLE 227A

A solution of the product from Example 200 C (670 mg, 1.68 mmol) andmCPBA (725 mg, 3.36 mmol) in CH₂Cl₂ (25 mL) was stirred for 1 hour. Thereaction was condensed and chromatographed on SiO₂ using 50% ethylacetate/hexanes as eluent, to yield 585 mg (81%) of the desiredcompound.

MS (DCI/NH₃) m/z 448 (M+NH₄)⁺.

EXAMPLE 227B6-(aminoiminomethyl)-4-[5-(ethylsulfonyl)-3-furanyl]-N-phenyl-2-naphthalenecarboxamide,monohydrochloride

The desired compound was prepared from Example 227A and the procedure ofExample 13.

MS (DCI/NH₃) m/z 448 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆) δ 1.29 (t, 3H),3.50 (q, 2H), 7.16 (t, 1H), 7.42 (t, 2H), 7.83 (d, 2H), 7.95 (dd, 1H),8.05 (s, 1H), 8.28 (s, 1H), 8.43 (d, 1H), 8.57 (s, 1H), 8.74 (s, 1H),8.79 (s, 1H), 9.19 (br s, 2H), 9.59 (br s, 2H), 10.61 (s, 1H); Anal.calcd for C₂₄H₂₂N₃SO₄.1.0 HCl.1.0 H₂O: C, 57.43; H, 4.82; N, 8.37.Found: C, 57.21; H, 5.04; N, 8.34.

EXAMPLE 2286-(aminoiminomethyl)-4-[5-(propylsulfonyl)-3-furanyl]-N-phenyl-2-naphthalenecarboxamide,monohydrochloride EXAMPLE 228A

The desired compound was prepared from the product from Example 201C bythe procedure of Example 227A.

MS (DCI/NH₃) m/z 462 (M+NH₄)⁺.

EXAMPLE 228B6-(aminoiminomethyl)-4-[5-(propylsulfonyl)-3-furanyl]-N-phenyl-2-naphthalenecarboxamide,monohydrochloride

The desired compound was prepared from Example 228A and the procedure ofExample 13.

MS (DCI/NH₃) m/z 462 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆) δ 1.03 (t, 3H),1.75 (qt, 2H), 3.48 (q, 2H), 7.16 (t, 1H), 7.41 (t, 2H), 7.84 (d, 2H),7.95 (dd, 1H), 8.05 (s, 1H), 8.28 (d, 1H), 8.42 (d, 1H), 8.58 (s, 1H),8.77 (s, 1H), 8.82 (s, 1H), 9.28 (br s, 2H), 9.63 (br s, 2H), 10.66 (s,1H); Anal. calc'd for C₂₅H₂₄N₃SO₄.1.0 HCl.1.5 H₂O: C, 57.20; H, 5.18; N,8.00. Found: C, 56.86; H, 5.08; N, 8.28.

EXAMPLE 2296-(aminoiminomethyl)-4-[5-[methylthio)methyl]-3-furanyl]-N-phenyl-2-naphthalenecarboxamide,monohydrochloride EXAMPLE 229A

To a solution of 2-trimethylsilyl-3-bromofuran (10.41 g, 47.5 mmol) inTHF (100 mL) at −78° C. was added a 1.5 M solution of LDA (34.8 mL,52.25 mmol), and the reaction was stirred at −78° C. for 1 hour. DMF(4.41 mL, 57.0 mmol) was then added, and the reaction was allowed towarm to room temperature and stirred for 1 hour. The reaction was pouredinto saturated aqueous NH₄Cl solution, and extracted with 3×dimethylether. The combined extracts were washed with brine, dried over Na₂SO₄,and condensed. The crude material was taken up in methanol (200 mL) andNaBH₄ (1.15 g, 24.0 mmol) was added in portions to the stirred solution.After 30 min, the solution was consensed, taken up in pH7 buffer, andextracted with 3×ethyl acetate. The combinied extracts were washed withbrine, dried over Na₂SO₄, and condensed. The crude product waschromatographed on SiO₂ using 30% ethyl acetate/hexanes as eluent, toyield 5.52 g (47%) of the desired compound.

MS (DCI/NH₃) m/z 250 (M+H)⁺.

EXAMPLE 229B

To a solution of the product from Example 229A (5.52 g, 22.15 mmol) andLiCl (1.03 g, 24.36 mmol) in DMF (60 mL) at 0° C. was added PCl₃ (2.12mL, 24.36 mmol), and the reaction was stirred at room temperature for 1hour. The reaction was poured into saturated aqueous NH₄Cl solution, andextracted with 3×dimethyl ether/hexanes. The combined extracts werewashed with 2×water, 2×brine, dried over Na₂SO₄, and condensed to yield4.70 g (79%) of the desired compound.

EXAMPLE 229C

A solution of the product from Example 229B (4.70 g, 17.56 mmol) andMeSNa (1.35 g, 19.3 mmol) in DMF (40 mL) was stirred at room temperaturefor 3 hours. The reaction was poured into saturated aqueous NaHCO₃solution, and extracted with 3×Diethyl ether. The combined extracts werewashed with brine, dried over Na₂SO₄, and condensed. The crude productwas chromatographed on SiO₂ using 30% ethyl acetate/hexanes as eluent,to yield 4.00 g (82%) of the desired compound.

EXAMPLE 229D

The desired compound was prepared form the product from Example 229C bythe procedure of Example 154B.

MS (DCI/NH₃) m/z 308 (Bu₃Sn+NH₄)⁺.

EXAMPLE 229E

The desired compound was prepared from the product from Example D andthe product from Example 152C by the procedure of Example 154C.

MS (DCI/NH₃) m/z 416 (M+NH₄)⁺.

EXAMPLE 229F6-(aminoiminomethyl)-4-[5-[methylthio)methyl]-3-furanyl]-N-phenyl-2-naphthalenecarboxamide,monohydrochloride

The desired compound was prepared from Example 229E and the procedure ofExample 144C.

MS (DCI/NH₃) m/z 416 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆) δ 2.15 (s, 3H),3.87 (s, 2H), 7.14 (t, 1H), 7.40 (t, 2H), 7.84 (d, 2H), 7.92 (dd, 1H),8.19 (d, 1H), 8.32 (s, 1H), 8.39 (d, 1H), 8.64 (s, 1H), 9.31 (br s, 2H),9.61 (br s, 2H), 10.62 (s, 1H); Anal. calc'd for C₂₄H₂₁N₃SO₂.1.4 HCl: C,61.79; H, 4.84; N, 9.01. Found: C, 61.83; H, 4.82; N, 9.13.

EXAMPLE 2306-(aminoiminomethyl)-4-[5-(methoxymethyl)-3-furanyl]-N-phenyl-2-naphthatenecarboxamide,monohydrochloride EXAMPLE 230A

The desired compound was prepared from 2-trimethylsinyl-3-bromofuran andchloromethyl methyl ether by the procedure of Example 154A.

EXAMPLE 230B

The desired compound was prepared from the product from Example 230A bythe procedure of Example 154B.

MS (DCI/NH₃) m/z 308 (Bu₃Sn+NH₄)⁺.

EXAMPLE 230C

The desired compound was prepared from the product from Example 230B andthe product from Example 152C by the procedure of Example 154C.

MS (DCI/NH₃) m/z 400 (M+NH₄)⁺.

EXAMPLE 230D6-(aminoiminomethyl)-4-[5-(methoxymethyl)-3-furanyl]-N-phenyl-2-naphthalenecarboxamide,monohydrochloride

The desired compound was prepared from Example 230C and the procedure ofExample 144C.

MS (DCI/NH₃) m/z 400 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆) δ 3.38 (s, 3H),4.49 (s, 2H), 7.14 (t, 1H), 7.18 (t, 1H), 7.40 (t, 2H), 7.84 (d, 2H),7.92 (dd, 1H), 8.19 (d, 1H), 8.38 (d, 1H), 8.42 (s, 1H), 8.64 (s, 1H),8.70 (s, 1H), 9.32 (br s, 2H), 9.62 (br s, 2H), 10.68 (s, 1H); Anal.calc'd for C₂₄H₂₁N₃O₃.2.8 HCl: C, 57.48; H, 4.78; N, 8.38. Found: C,57.40; H, 4.44; N, 8.38.

EXAMPLE 2316-(aminoiminomethyl)-4-[5-(methylsulfonyl)-3-furanyl]-N-phenyl-2-naphthalenecarboxamide,mono(trifluoroacetate)(salt) EXAMPLE 231A

The desired compound was prepared from the product from Example 152C bythe procedure of Example 227A.

MS (DCI/NH₃) m/z 434 (M+NH₄)⁺.

EXAMPLE 231B6-(aminoiminomethyl)-4-[5-(methylsulfonyl)-3-furanyl]-N-phenyl-2-naphthalenecarboxamide,mono(trifluoroacetate)(salt)

The desired compound was prepared from Example 231A and the procedure ofExample 13.

MS (DCI/NH₃) m/z 434 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆) δ 3.44 (s, 3H),7.16 (t, 1H), 7.40 (t, 2H), 7.82 (d, 2H), 7.91 (s, 1H), 7.95 (dd, 1H),8.00 (s, 1H), 8.36 (s, 1H), 8.43 (d, 1H), 8.57 (s, 1H), 8.75 (s, 2H),9.18 (br s, 2H), 9.53 (br s, 2H); Anal. calc'd for C₂₃H₁₉N₃SO₄.1.0C₂HF₃O₂: C, 54.84; H, 3.68; N, 7.67. Found: C, 55.05; H, 3.74; N, 7.75.

EXAMPLE 2326-(aminoiminomethyl)-4-[5-(ethythio)tetrahydro-3-furanyl]-N-phenyl-2-naphthalenecarboxamide,monohydrochloride EXAMPLE 232A

The desired compound was prepared from the product from Example 152A bythe procedure of Example 62A.

MS (DCI/NH₃) m/z 315 (M+NH₄)⁺.

EXAMPLE 232B

A solution of the product from Example 232A (1.62 g, 5.45 mmol),ethanethiol (2.2 mL), and conc. HCl (0.80 mL) in CHCl₃ (22 mL) wasstirred at room temperature for 3 hours and condensed. The crude productwas chromatographed on SiO₂ using 15% ethyl acetate/hexanes as eluent,to yield 1.20 g (65%) of the desired compound.

MS (DCI/NH₃) m/z 359 (M+NH₄)⁺.

EXAMPLE 232C

The desired compound was prepared from the product from Example 232B bythe procedure of Example 152B.

MS (DCI/NH₃) m/z 345 (M+NH₄)⁺.

EXAMPLE 232D

The desired compound was prepared from the product from Example 232C bythe procedure of Example 207C.

MS (DCI/NH₃) m/z 420 (M+NH₄)⁺.

EXAMPLE 232E6-(aminoiminomethyl)-4-[5-(ethythio)tetrahydro-3-furanyl]-N-phenyl-2-naphthalenecarboxamide,monohydrochloride

The desired compound was prepared from Example 232D and the procedure ofExample 144C.

MS (DCI/NH₃) m/z 420 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆) δ 1.18 (dt, 3H),2.42 (m, 1H), 3.50 (dq, 2H), 3.74 (m, 1H), 3.93 (m, 1h), 4.39 (m, 1H),4.54 (m, 1H), 5.38 (dd, 0.5H), 5.42 (dd, 0.5H), 7.14 (t, 1H) 7.40 (t,2H), 7.82 (d, 2H), 7.95 (d, 1H), 8.06 (s, 0.5H), 8.20 (s, 0.5H), 8.32(d, 1H), 8.60 (s, 1H), 8.71 (s, 0.5H), 8.80 (s, 0.5H), 9.32 (br s, 2H),9.62 (br s, 2H), 10.59 (br s, 1H); Anal. calc'd for C₂₄H₂₅N₃O₂S.1.0 HCl:C, 63.22; H, 5.75; N, 9.21. Found: C, 62.93; H, 5.58; N, 9.01.

What is claimed is:
 1. A compound having the formula

or a pharmaceutically acceptable salt, ester, or prodrug thereof,wherein A is —L_(A)R_(A), wherein L_(A) is —NR₂C(X)— wherein X is O andR₂ is selected from the group consisting of (a) hydrogen, (b) alkyl ofone to six carbon atoms, (c) alkenyl of three to six carbon atoms, (d)alkynyl of three to six carbon atoms, (e) aryl, (f) arylalkyl, whereinthe alkylene group is of one to six carbon atoms, (g) cycloalkyl ofthree to eight carbon atoms, and (h) cycloalkylalkyl, wherein thecycloalkyl group is of three to eight carbon atoms, and the alkylenegroup is of one to ten carbon atoms, wherein L_(A) is depicted with theright end being the end which is attached to the naphthyl ring and theleft end being the end which is attached to R_(A), and R_(A) is selectedfrom the group consisting of aryl and heterocycle, wherein the aryl orthe heterocycle are optionally substituted; B is hydrogen; and C is—L_(C)R_(C), wherein L_(C) is selected from the group the groupconsisting of (a) a covalent bond and (b) —NR₁—, wherein R₁ is selectedfrom the group consisting of (i) hydrogen and (ii) alkyl of one to sixcarbon atoms, and R_(C) is heterocycle, wherein the heterocycle isoptionally substituted.
 2. A compound selected from the group consistingof6-(aminoiminomethyl)-4-(3-furanyl)-N-[4-(trifluoromethyl)phenyl]-2-naphthalenecarboxamide,mono(trifluoroacetate) salt;6-(aminoiminomethyl)-4-(3-furanyl)-N-(4-pyridinyl)-2-naphthalenecarboxamide,dihydrochloride;6-(aminoiminomethyl)-4-(3-furanyl)-N-(1H-pyrazol-3-yl)-2-naphthalenecarboxamide,dihydrochloride;6-(aminoiminomethyl)-4-(3-furanyl)-N-(3-pyridinyl)-2-naphthalenecarboxamide,dihydrochloride;6-(aminoiminomethyl)-4-(3-furanyl)-N-(2-pyridinyl)-2-naphthalenecarboxamide,dihydrochloride;6-(aminoiminomethyl)-4-(3-furanyl)-N-phenyl-2-naphthalenecarboxamide,monohydrochloride;6-(aminoiminomethyl)-4-[1-(methylsulfonyl)-1H-pyrazol-4-yl]-N-phenyl-2-naphthalenecarboxamide,monohydrochloride;6-(aminoiminomethyl)-4-[5-(methylthio)-3-furanyl)]-N-phenyl-2-naphthalenecarboxamide,monohydrochloride;6-(aminoiminomethyl)-N-[4-(aminomethyl)phenyl]-4-(2-pyrimidinylamino)-2-naphthalenecarboxamide,tris(trifluoroacetate) salt;6-(aminoiminomethyl)-N-phenyl-4-(2-pyrimidinylamino)-2naphthalenecarboxamide,mono(trifluoroacetate) salt;N-[(4-(aminomethyl)phenyl]-6-[amino(hydroxyimino)methyl]-4-(2-pyrimidinylamino)-2-naphthalenecarboxamide,bis(trifluoroacetate) salt;6-(aminoiminomethyl)-N-[4-(hydroxymethyl)phenyl]-4-(2-pyrimidinylamino)-2-naphthalenecarboxamide,mono(trifluoroacetate) salt;6-(aminoiminomethyl)-N-phenyl-4-(tetrahydro-3-furanyl)-2-naphthalenecarboxamide,monohydrochloride;6-[amino(hydroxyimino)methyl]-N-phenyl-4-(2-pyrimidinylamino)-2-naphthalenecarboxamide;6-(aminoiminomethyl)-4-[5-(ethylthio)-3-furanyl]-N-phenyl-2-naphthalenecarboxamide,monohydrochloride;6-(aminoiminomethyl)-4-[5-(propylthio)-3-furanyl]-N-phenyl-2-naphthalenecarboxamide,monohydrochloride;6-(aminoiminomethyl)-N-phenyl-4-(2-pyrrolidinyl)-2-naphthalenecarboxamide,mono(trifluoroacetate) salt;6-(aminoiminomethyl)-4-[5-(ethylsulfonyl)-3-furanyl]-N-phenyl-2-naphthalenecarboxamide,monohydrochloride;6-(aminoiminomethyl)-4-[5-(propylsulfonyl)-3-furanyl]-N-phenyl-2-naphthalenecarboxamide,monohydrochloride;6-(aminoiminomethyl)-4-[5-[methylthio)methyl]-3-furanyl]-N-phenyl-2-naphthalenecarboxamide,monohydrochloride;6-(aminoiminomethyl)-4-[5-(methoxymethyl)-3-furanyl]-N-phenyl-2-naphthalenecarboxamide,monohydrochloride;6-(aminoiminomethyl)-4-[5-(methylsulfonyl)-3-furanyl]-N-phenyl-2-naphthalenecarboxamide,mono(trifluoroacetate) salt; and6-(aminoiminomethyl)-4-[5-(ethythio)tetrahydro-3-furanyl]-N-phenyl-2-naphthalenecarboxamide,monohydrochloride.
 3. A method for inhibiting urokinase in a mammal inneed of such treatment, comprising adminstering to the mammal atherapeutically effective amount of a compound of claim
 1. 4. Acomposition for inhibiting urokinase comprising both a pharmaceuticalcarrier and a therapeutically effective amount of a compound of claim 1.5. A compound, or a pharmaceutically acceptable salt or prodrug thereof,which is6-(aminoiminomethyl)-N-[4-(aminomethyl)phenyl]-4-(2-pyrimidinylamino)-2-naphthalenecarboxamide.